Expression of intercellular adhesion molecule (ICAM)-1 or ICAM-2 is critical in determining sensitivity of pancreatic cancer cells to cytolysis by human gammadelta-T cells: implications in the design of gammadelta-T-cell-based immunotherapies for pancreatic cancer.
Liu Zhiyong,Guo Ben,Lopez Richard D
Journal of gastroenterology and hepatology
BACKGROUND AND AIMS:gammadelta-T cells can recognize and kill malignant cells, particularly those of epithelial origin, through mechanisms which do not require the recognition of tumor-specific antigens (innate immune response). This natural ability of gammadelta-T cells to kill tumor cells in a tumor antigen-independent manner provides a strong rationale for developing clinical trials designed to exploit the innate antitumor properties of gammadelta-T cells. METHODS:In vitro studies were carried out to asses the sensitivity of pancreatic cancer cells (MIA PaCa2, BxPC-3, PANC-1) to killing by ex vivo expanded human gammadelta-T cells. RESULTS:The capacity of gammadelta-T cells to bind to as well as to kill pancreatic cancer cells correlated with the degree of surface expression of key intercellular adhesion molecules (ICAM) present on pancreatic cancer cells. Moreover, pancreatic cancer cells expressing neither ICAM-1 nor ICAM-2 were bound poorly by gammadelta-T cells and were found to be resistant to gammadelta-T-cell killing. However, upon transfection of resistant cells with ICAM-1 or ICAM-2, gammadelta-T cells were then able to bind to and subsequently kill these cells. CONCLUSION:In vitro, the expression of ICAM-1 or ICAM-2 on human pancreatic cancer cells is critically important in determining the extent to which these cells are sensitive to killing by human gammadelta-T cells. Accordingly, in ongoing and future clinical studies using gammadelta-T cells for the treatment of a variety of epithelial-derived solid tumors-including pancreatic cancer-interventions intended to modulate ICAM expression on tumor cells may become important adjuncts to gammadelta-T-cell-based immunotherapies.
10.1111/j.1440-1746.2008.05668.x
[Anti-pancreatic cancer effects of human peripheral gammadeltaT cells in a mouse tumor model].
Dai Meng-hua,He Wei,Zhao Yu-pei,Xu Chun-ping
Zhonghua wai ke za zhi [Chinese journal of surgery]
OBJECTIVE:To explore the adoptive immunotherapy effect of peripheral gammadeltaT cells in pancreatic cancer nude mice model. METHODS:Thirty BALB/c nude mice were inoculated subcutaneously 5 x 10(5) Cap-1 cells to regularly developed hypodermal tumors, and then divided into 3 groups randomly, gammadeltaT cells, alphabetaT cells and control group. 2.5 x 10(6) gammadeltaT cells or alphabetaT cells or 100 microl RPMI-1640 were respectively injected into abdominal cavity of mice, combined with 10(4) U rhIL-2 for 3 times. Tumor volume, the survival rate and anti-carcinogenic rate of three groups were compared. RESULTS:Eight control nude mice developed hypodermal tumors, which progressively increased in size, and animals had a mean survival of 88 d. Nine nude mice in gammadeltaT cells group and eight in alphabetaT cells group developed tumors (P > 0.05). Tumor growth was arrested and tumor size was reduced remarkably in gammadeltaT cells group. Mean survival was increased to 113 d with less rate of tumor metastasis and more cases of tumor necrosis in gammadeltaT cells group when compared with alphabetaT cells group and controls. CONCLUSIONS:The anti-tumor effects of gammadeltaT cells against pancreatic cancer are better than those of alphabetaT cells and control groups, and might be promising in the adoptive immunotherapy of pancreatic cancer.
Ex vivo expanded human Vgamma9Vdelta2+ gammadelta-T cells mediate innate antitumor activity against human prostate cancer cells in vitro.
Liu Zhiyong,Guo Ben L,Gehrs Bradley C,Nan Li,Lopez Richard D
The Journal of urology
PURPOSE:We have previously identified a CD2 mediated, interleukin-12 dependent signaling pathway that inhibits activation induced cell death in mitogen stimulated human gammadelta-T cells, permitting the large-scale expansion of these cells. Herein we report the innate antitumor activity of expanded human Vgamma9Vdelta2+ gammadelta-T cells against human prostate cancer cells. MATERIALS AND METHODS:Apoptosis resistant human gammadelta-T cells were expanded in vitro from cultured human peripheral blood mononuclear cells and then enriched to high purity by immunomagnetic separation. In vitro cytotoxicity of expanded gammadelta-T cells was measured against human prostate cancer cell lines using standard cytotoxicity assays. RESULTS:gammadelta-T cells derived from various donors consistently showed lytic activity against the prostate cancer cell lines DU-145 and PC-3 but not LNCaP. mAbs against Vgamma9 or Vdelta2 T-cell receptor chains as well as mAb against intercellular adhesion molecule-1 (ICAM-1) or CD18, the beta subunit of ICAM-1 counter receptors, blocked gammadelta-T cell mediated killing of prostate cancer cells. gammadelta-T cells lysed prostate cancer cell lines largely through the perforin/granzyme pathway. CONCLUSIONS:Ex vivo, expanded human Vgamma9Vdelta2+ gammadelta-T cells are able innately to recognize and kill certain human prostate tumor cell lines in vitro. The recognition and killing of prostate cancer cells occurs in a gammadelta-T-cell receptor dependent manner and it also appears to involve interactions between ICAM-1 and CD18. Because apoptosis resistant human Vgamma9Vdelta2+ gammadelta-T cells can readily be expanded to large numbers (clinical scale), these findings must be considered in the context of developing adoptive immunotherapy strategies to exploit gammadelta-T cell innate immune responses to prostate cancer.
10.1097/01.ju.0000154355.45816.0b
Adoptively transferred ex vivo expanded gammadelta-T cells mediate in vivo antitumor activity in preclinical mouse models of breast cancer.
Beck Benjamin H,Kim Hyung-Gyoon,Kim Hyunki,Samuel Sharon,Liu Zhiyong,Shrestha Robin,Haines Hilary,Zinn Kurt,Lopez Richard D
Breast cancer research and treatment
In contrast to antigen-specific alphabeta-T cells (adaptive immune system), gammadelta-T cells can recognize and lyse malignantly transformed cells almost immediately upon encounter in a manner that does not require the recognition of tumor-specific antigens (innate immune system). Given the well-documented capacity of gammadelta-T cells to innately kill a variety of malignant cells, efforts are now actively underway to exploit the antitumor properties of gammadelta-T cells for clinical purposes. Here, we present for the first time preclinical in vivo mouse models of gammadelta-T cell-based immunotherapy directed against breast cancer. These studies were explicitly designed to approximate clinical situations in which adoptively transferred gammadelta-T cells would be employed therapeutically against breast cancer. Using radioisotope-labeled gammadelta-T cells, we first show that adoptively transferred gammadelta-T cells localize to breast tumors in a mouse model (4T1 mammary adenocarcinoma) of human breast cancer. Moreover, by using an antibody directed against the gammadelta-T cell receptor (TCR), we determined that localization of adoptively transferred gammadelta-T cells to tumor is a TCR-dependant process. Additionally, biodistribution studies revealed that adoptively transferred gammadelta-T cells traffic differently in tumor-bearing mice compared to healthy mice with fewer gammadelta-T cells localizing into the spleens of tumor-bearing mice. Finally, in both syngeneic (4T1) and xenogeneic (2Lmp) models of breast cancer, we demonstrate that adoptively transferred gammadelta-T cells are both effective against breast cancer and are otherwise well-tolerated by treated animals. These findings provide a strong preclinical rationale for using ex vivo expanded adoptively transferred gammadelta-T cells as a form of cell-based immunotherapy for the treatment of breast cancer. Additionally, these studies establish that clinically applicable methods for radiolabeling gammadelta-T cells allows for the tracking of adoptively transferred gammadelta-T cells in tumor-bearing hosts.
10.1007/s10549-009-0527-6
[Cytotoxic effects of γδT cells on bladder cancer cells and expression of MICA/B in bladder cancer].
Zhou J H,Wang D,Wang H R,Hou X L,Yu W D,Xu K X,Hu H
Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences
OBJECTIVE:To explore the role of γδT cells against bladder cancer and to detect the expression of stress proteins MICA/B recognized by γδT cells in bladder cancer. METHODS:γδT cells from peripheral blood drawn from 6 bladder cancer patients with pamidronate stimulating were expanded. Flow cytometry was used to detect the purity and expansion folds of γδT cells, and the expression of CD107a on γδT cells after PMA/ionomycin stimulated. The cytotoxicity assay was carried out to test the cytotoxicity of γδT cells against human bladder cancer cell lines. The expression of MICA/B on bladder cancer cell lines and in bladder cancer tissues were detected through flow cytometry and immunohistochemistry respectively. RESULTS:γδT cells from peripheral blood drawn from 6 bladder cancer patients were successfully expanded. The purity was 75%-94% and the expansion folds were 109-371 times. After being stimulated by PMA/ionomycin, the proportion of CD107a+ γδT cells increased significantly, reaching 40%-82%. γδT cells from the 6 bladder cancer patients showed obvious cytotoxic effects on 3 human bladder cancer cell lines which was enhanced as the effector: the target ratio increased. MICA/B were detected both in 3 bladder cancer cell lines and in 26 bladder cancer tissues. The staining score of MICA/B in invasive bladder cancer was slightly higher than that in non-invasive bladder cancer, and in advanced bladder cancer was higher than that in low grade bladder cancer, but the statistical analysis showed that the staining score of MICA/B was no significant correlation between the tissue and the tumor stages and grades. CONCLUSION:γδT cells from the peripheral blood of the bladder cancer patients could be successfully expanded in vitro, and showed significant anti-bladder cancer effect. MICA/B were detected both in bladder cancer cell lines and in bladder cancer tissues. The statistical analysis showed that there was no significant correlation between the staining scores of MICA/B in the tissue and the tumor stages and grades.
Wnt pathway activator TWS119 enhances the proliferation and cytolytic activity of human γδT cells against colon cancer.
Chen Yong-Qiang,Zheng Lu,Aldarouish Mohanad,Zhou Zhong-Hai,Pan Ning,Liu Jun-Quan,Chen Fu-Xing,Wang Li-Xin
Experimental cell research
γδT cells are a distinct T-cell subset that display unique characteristics regarding T-cell receptor gene usage, tissue tropism and antigen recognition. Adoptive γδT cell transfer therapy has recently been gaining importance as an efficient approach in cancer immunotherapy. However, exploiting γδT cell response for tumour immunotherapy is a challenge due to cell numbers, activities and differentiation states that minimize the clinical therapeutic effects. Previous studies have indicated that the wnt/β-catenin signalling pathway plays a crucial role in the differentiation, survival and enhancement of the immune response of T lymphocytes. In this study, we sought to evaluate whether the activation of the wnt/β-catenin pathway through inhibition of glycogen synthase kinase-3β (GSK-3β) using 4,6-disubstituted pyrrolopyrimidine (TWS119) could be an efficient strategy to improve the proliferation, differentiation and cytolytic activity of γδT cells against colon cancer cells. Remarkably, we found that TWS119 significantly enhanced the proliferation and survival of γδT cells via activation of the mammalian target of rapamycin (mTOR) pathway, upregulation of the expression of the anti-apoptotic protein Bcl-2 and inhibition of cleaved caspase-3 in addition to the Wnt pathway. Our results also showed that enhancement of the cytolytic activity of γδT cells against human colon cancer cells by TWS119 was chiefly associated with upregulation of the expression of perforin and granzyme B in vitro and in vivo. Additionally, TWS119 can induce the expression of CD62L or CCR5 to generate a population of CD62LγδT or CCR5γδT cells in a dose-dependent manner. These findings suggested that TWS119 could be a useful complementary agent for improving γδT cell-based immunotherapy.
10.1016/j.yexcr.2017.11.003
γδT Cells Suppress Liver Fibrosis via Strong Cytolysis and Enhanced NK Cell-Mediated Cytotoxicity Against Hepatic Stellate Cells.
Liu Meifang,Hu Yuan,Yuan Yi,Tian Zhigang,Zhang Cai
Frontiers in immunology
Liver fibrosis is the excessive accumulation of extracellular matrix proteins, resulting from maladaptive wound healing responses to chronic liver injury. γδT cells are important in chronic liver injury pathogenesis and subsequent liver fibrosis; however, their role and underlying mechanisms are not fully understood. The present study aims to assess whether γδT cells contribute to liver fibrosis regression. Using a carbon tetrachloride (CCl)-induced murine model of liver fibrosis in wild-type (WT) and γδT cell deficient (TCRδ) mice, we demonstrated that γδT cells protected against liver fibrosis and exhibited strong cytotoxicity against activated hepatic stellate cells (HSCs). Further study show that chronic liver inflammation promoted hepatic γδT cells to express NKp46, which contribute to the direct killing of activated HSCs by γδT cells. Moreover, we identified that an IFNγ-producing γδT cell subset (γδT1) cells exhibited stronger cytotoxicity against activated HSCs than the IL-17-producing subset (γδT17) cells upon chronic liver injury. In addition, γδT cells promoted the anti-fibrotic ability of conventional natural killer (cNK) cells and liver-resident NK (lrNK) cells by enhancing their cytotoxicity against activated HSCs. The cell crosstalk between γδT and NK cells was shown to depend partly on co-stimulatory receptor 4-1BB (CD137) engagement. In conclusion, our data confirmed the protective effects of γδT cells, especially the γδT1 subset, by directly killing activated HSCs and increasing NK cell-mediated cytotoxicity against activated HSCs in CCl-induced liver fibrosis, which suggest valuable therapeutic targets to treat liver fibrosis.
10.3389/fimmu.2019.00477
Differential requirement of RasGRP1 for γδ T cell development and activation.
Chen Yong,Ci Xinxin,Gorentla Balachandra,Sullivan Sarah A,Stone James C,Zhang Weiguo,Pereira Pablo,Lu Jianxin,Zhong Xiao-Ping
Journal of immunology (Baltimore, Md. : 1950)
γδ T (γδT) cells belong to a distinct T cell lineage that performs immune functions different from αβ T (αβT) cells. Previous studies established that Erk1/2 MAPKs are critical for positive selection of αβT cells. Additional evidence suggests that increased Erk1/2 activity promotes γδT cell generation. RasGRP1, a guanine nucleotide-releasing factor for Ras, plays an important role in positive selection of αβT cells by activating the Ras-Erk1/2 pathway. In this article, we demonstrate that RasGRP1 is critical for TCR-induced Erk1/2 activation in γδT cells, but it exerts different roles for γδT cell generation and activation. Deficiency of RasGRP1 does not obviously affect γδT cell numbers in the thymus, but it leads to increased γδT cells, particularly CD4(-)CD8(+) γδT cells, in the peripheral lymphoid organs. The virtually unhindered γδT cell development in the RasGRP1(-/-) thymus proved to be cell intrinsic, whereas the increase in CD8(+) γδT cells is caused by non-cell-intrinsic mechanisms. Our data provide genetic evidence that decreased Erk1/2 activation in the absence of RasGRP1 is compatible with γδT cell generation. Although RasGRP1 is dispensable for γδT cell generation, RasGRP1-deficient γδT cells are defective in proliferation following TCR stimulation. Additionally, RasGRP1-deficient γδT cells are impaired to produce IL-17 but not IFNγ. Together, these observations revealed that RasGRP1 plays differential roles for γδ and αβ T cell development but is critical for γδT cell proliferation and production of IL-17.
10.4049/jimmunol.1103272
Identification of prognostic factors for γδT cell immunotherapy in patients with solid tumor.
Takimoto Rishu,Miyashita Tomoharu,Mizukoshi Eishiro,Kamigaki Takashi,Okada Sachiko,Ibe Hiroshi,Oguma Eri,Naitoh Keiko,Yasumoto Kosei,Makita Kaori,Tomita Katsuro,Goto Shigenori
Cytotherapy
BACKGROUND AIMS:Activated γδT cells have been shown to exhibit cytotoxicity against tumor cells. However, the efficacy of γδT cell immunotherapy for a large number of patients with solid tumors remains unclear. In this study, we examined the efficacy of γδT cell immunotherapy using in vitro-activated γδT lymphocytes in combination with standard therapies in terms of the survival of patients with solid tumors, and determined prognostic factor for γδT cell immunotherapy. METHODS:131 patients enrolled in this study received γδT cell immunotherapy with or without standard therapies. Their overall survival was analyzed by the Kaplan-Meier with log-rank test and Cox regression methods. Immunological analysis was performed by flow cytometry (FCM) before and after six cycles of γδT cell immunotherapy. RESULTS:Multivariable analysis revealed that patients who showed stable disease (SD) and partial response (PR) to γδT cell immunotherapy showed better prognosis than those with a progressive disease (PD) (P = 0.0269, hazard ratio [HR], 0.410, 95% confidence interval [CI], 0.190-0.901). Furthermore, when immunological parameters were examined by FCM, the high Vγ9/γδT ratio (i.e., the high purity of the Vγ9 cells within the adoptively transferred γδT cells) before treatment was found to be a good prognostic factor for γδT cell immunotherapy (P = 0.0142, HR, 0.328, 95% CI, 0.125-0.801). No serious adverse events were reported during γδT cell immunotherapy. CONCLUSION:Thus, γδT cell immunotherapy might extend the survival of patients with solid tumors.
10.1016/j.jcyt.2020.02.008
Tumor-infiltrating γδT cells predict prognosis and adjuvant chemotherapeutic benefit in patients with gastric cancer.
Wang Jieti,Lin Chao,Li He,Li Ruochen,Wu Yifan,Liu Hao,Zhang Heng,He Hongyong,Zhang Weijuan,Xu Jiejie
Oncoimmunology
: Tumor-infiltrating γδT cells (γδTILs) have different prognostic value and functions among various cancers. The aim of the present study was to evaluate the effect of γδTILs in gastric cancer. : A discovery set (n = 190) and a validation set (n = 273) were involved in this study. Patients with TNM II and III disease were used to predict response to 5-fluorouracil (5-FU)-based adjuvant chemotherapy (ACT) in both sets. γδTILs were defined as intense (γδT cells≥ 5/HPF) versus nonintense (γδT cells<5/HPF). Kaplan-Meier curve was plotted to analysis survival. Hazard ratio (HR) and 95%CI associated with γδTILs were evaluated by multivariable Cox models. : The prognostic value of γδTILs in the discovery set (HR, 0.193; 95%CI, 0.097-0.383; P<0.001) was confirmed in the validation set (HR, 0.442; 95%CI, 0.251-0.779; P = 0.005) for overall survival (OS). Patients whose tumors with γδT cells≥ 5/HPF could benefit from ACT, with a reduced risk of compromised survival compared with those with γδT cells<5/HPF (HR, 0.086; 95%CI, 0.023-0.327; P<0.001 in discovery set; and HR, 0.077; 95%CI, 0.023-0.256; P<0.001 in validation set). : The present study shows that intense γδT cells infiltration is an independent prognostic factor in patients with gastric cancer and is predictive of a survival benefit from adjuvant chemotherapy in patients with TNM II and III disease.
10.1080/2162402X.2017.1353858
Gammadelta T cells as a predictor of surgical relapse of Crohn's disease.
Andreu-Ballester J C,Catalán-Serra I,Gil-Borrás R,Marqués-García P,García-Ballesteros C,López Chuliá F,Cuéllar C
Clinics and research in hepatology and gastroenterology
BACKGROUND:We recently demonstrated a decrease in the overall lymphocyte population in the peripheral blood of patients with CD compared to healthy controls and this decrease is more evident in γδ T lymphocytes. The percentages of T cell subsets could reflect the risk of surgical relapse in CD patients. The aim of this study is to study the correlation between αβ and γδ T cell subsets in the peripheral blood of patients with CD and the risk for surgery during follow up. METHODS:A prospective study of 102 patients with CD compared with 102 healthy subjects (control group) matched by age and sex was conducted. Lymphocytic populations of CD3+, CD4+, CD8+, CD56+, and αβ and γδ T cell subsets were measured in the peripheral blood of all participants. RESULTS:We found evidence of a relationship between lower γδ T cell levels and risk of surgical relapse in CD. The lowest subsets observed in CD patients with surgical relapse were CD3+γδ, CD3+CD8+γδ and CD3+CD56+γδT cells. We observed a relationship between a decrease in γδ T cells and the most severe forms of the disease. The lowest levels of CD3+γδ and CD3+CD8+γδT cells were observed in the fistulizing phenotype. CONCLUSIONS:The deficit of γδ T cells was related with the severity and the risk for surgical relapse in CD patients. Patients with CD3+γδ deficit were more prone to surgery than patients without this deficit. These results suggest that γδ T cells could be used as markers of poor prognosis of CD following the diagnosis of the disease.
10.1016/j.clinre.2019.11.003
γδT Cells Induce the Inflammatory Response of Human Fibroblast-Like Synoviocytes Directly or by Stimulating B Cells to Activate IL-17/STAT3 Signaling Pathway.
International archives of allergy and immunology
INTRODUCTION:Rheumatoid arthritis (RA) combined with hashimoto thyroiditis (HT) is an important cause of various fatal comorbidities of RA. There is no precise conclusion about the cause of this disease. METHODS:Peripheral blood and synovial tissue were collected from healthy participants, patients with RA, and patients with both RA and HT. Immunofluorescence staining and Pearson correlation analysis were used to detect the levels of γδTCR and the correlation between IL-17 and p-STAT3, respectively. ELISA, chemiluminescence assays, qRT-PCR and Western blot were performed to detect the levels of IgG, IgM, IFN-γ, IL-1β, TNF-α, Tg-Ab, Tpo-Ab, IL-17, IL-2, p-SATA3, and STAT3, respectively. RESULTS:There was increased proportion of γδT cells, IL-17, and p-STAT3 levels in RA and HT patients. IL-17 was positively correlated with p-STAT3. γδT cells significantly promoted the expression of IgG, Tg-Ab, Tpo-Ab, and IL-17. When γδT and human fibroblast-like synoviocytes (FLSs) were co-cultured, the levels of IL-2, IFN-γ, IL-1β, TNF-α, and IL-17 were increased, and the IL-17/STAT3 signaling pathway was activated. When IL-17-silenced γδT cells and STAT3-silenced FLSs were co-cultured, the levels of IL-1β and TNF-α in FLSs were significantly decreased. Furthermore, when STAT3-silenced FLSs were added to the co-culture medium of B cells and γδT cells, the levels of IL-1β and TNF-α were also decreased significantly. CONCLUSION:γδT cells induced RA directly or by stimulating B cells to activate STAT3 through IL-17.
10.1159/000539703
Hypoxia regulates the differentiation and anti-tumor effector functions of γδT cells in oral cancer.
Sureshbabu S K,Chaukar D,Chiplunkar S V
Clinical and experimental immunology
Hypoxia within the tumor microenvironment (TME) is a key factor contributing to immunosuppression in tumors, co-relating with poor treatment outcome and decreased overall survival in advanced oral cancer (OC) patients. Vδ2 is a dominant subset of gamma delta T cells (γδT cells) present in the peripheral blood which exhibits potent anti-tumor cytotoxicity and is evolving as a key player of anti-cancer cellular therapy. However, the fate of γδT cells in hypoxic oral tumors remains elusive. In the present study, we compared the effect of hypoxia (1% O ) and normoxia (21% O ) on the expansion, proliferation, activation status, cytokine secretion and cytotoxicity of γδT cells isolated from OC patients and healthy individuals. Hypoxia-exposed γδT cells exhibited reduced cytotoxicity against oral tumor cells. Our data demonstrated that hypoxia reduces the calcium efflux and the expression of degranulation marker CD107a in γδT cells, which explains the decreased anti-tumor cytotoxicity of γδT cells observed under hypoxia. Hypoxia-exposed γδT cells differentiated to γδT17 [γδ T cells that produce interleukin (IL)-17] cells, which corroborated our observations of increased γδT17 cells observed in the oral tumors. Co-culture of γδT cells with CD8 T cells in the presence of hypoxia showed that programmed cell death ligand 1 (PD-L1) γδT cells brought about apoptosis of programmed cell death 1 (PD-1) CD8 T cells which could be significantly reversed upon blocking PD-1. Thus, future immunotherapeutic treatment modality for oral cancer may use a combined approach of blocking the PD-1/PD-L1 signaling and targeting hypoxia-inducible factor 1α, which may help in reversing hypoxia-induced immunosuppression.
10.1111/cei.13436
Intrinsically altered lung-resident γδT cells control lung melanoma by producing interleukin-17A in the elderly.
Cheng Min,Chen Yongyan,Huang Dake,Chen Wen,Xu Weiping,Chen Yin,Shen Guodong,Xu Tingjuan,Shen Gan,Tian Zhigang,Hu Shilian
Aging cell
Cancer is an age-associated disease, potentially related to the altered immune system of elderly individuals. However, cancer has gradually decreased incidence in the eldest globally such as the most common lung cancer, the mechanisms of which remain to be elucidated. In this study, it was found that the number of lung-resident γδT cells was significantly increased with altered gene expression in aged mice (20-24 months) versus young mice (10-16 weeks). Aged lung Vγ4 and Vγ6 γδT cells predominantly produced interleukin-17A (IL-17A), resulting in increased levels in the serum and lungs. Moreover, the aged mice exhibited smaller tumors and reduced numbers of tumor foci in the lungs after challenge with intravenous injection of B16/F10 melanoma cells compared with the young mice. Aged lung Vγ4 and Vγ6 γδT cells were highly cytotoxic to B16/F10 melanoma cells with higher expression levels of CD103. The markedly longer survival of the challenged aged mice was dependent on γδT17 cells, since neutralization of IL-17A or depletion of indicated γδT cells significantly shortened the survival time. Consistently, supplementation of IL-17A significantly enhanced the survival time of young mice with lung melanoma. Furthermore, the anti-tumor activity of aged lung γδT17 cells was not affected by alterations in the load and composition of commensal microbiota, as demonstrated through co-housing of the aged and young mice. Intrinsically altered lung γδT17 cells underlying age-dependent changes control lung melanoma, which will help to better understand the lung cancer progression in the elderly and the potential use of γδT17 cells in anti-tumor immunotherapy.
10.1111/acel.13099
Differential Roles of the mTOR-STAT3 Signaling in Dermal γδ T Cell Effector Function in Skin Inflammation.
Cai Yihua,Xue Feng,Qin Hui,Chen Xu,Liu Na,Fleming Chris,Hu Xiaoling,Zhang Huang-Ge,Chen Fuxiang,Zheng Jie,Yan Jun
Cell reports
Dermal γδT cells play critical roles in skin homeostasis and inflammation. However, the underlying molecular mechanisms by which these cells are activated have not been fully understood. Here, we show that the mechanistic or mammalian target of rapamycin (mTOR) and STAT3 pathways are activated in dermal γδT cells in response to innate stimuli such as interleukin-1β (IL-1β) and IL-23. Although both mTOR complex 1 (mTORC1) and mTORC2 are essential for dermal γδT cell proliferation, mTORC2 deficiency leads to decreased dermal γδT17 cells. It appears that mitochondria-mediated oxidative phosphorylation is critical in this process. Notably, although the STAT3 pathway is critical for dermal Vγ4T17 effector function, it is not required for Vγ6T17 cells. Transcription factor IRF-4 activation promotes dermal γδT cell IL-17 production by linking IL-1β and IL-23 signaling. The absence of mTORC2 in dermal γδT cells, but not STAT3, ameliorates skin inflammation. Taken together, our results demonstrate that the mTOR-STAT3 signaling differentially regulates dermal γδT cell effector function in skin inflammation.
10.1016/j.celrep.2019.05.019
γδT cells suppress inflammation and disease during rhinovirus-induced asthma exacerbations.
Mucosal immunology
Most asthma exacerbations are triggered by virus infections, the majority being caused by human rhinoviruses (RV). In mouse models, γδT cells have been previously demonstrated to influence allergen-driven airways hyper-reactivity (AHR) and can have antiviral activity, implicating them as prime candidates in the pathogenesis of asthma exacerbations. To explore this, we have used human and mouse models of experimental RV-induced asthma exacerbations to examine γδT-cell responses and determine their role in the immune response and associated airways disease. In humans, airway γδT-cell numbers were increased in asthmatic vs. healthy control subjects during experimental infection. Airway and blood γδT-cell numbers were associated with increased airways obstruction and AHR. Airway γδT-cell number was also positively correlated with bronchoalveolar lavage (BAL) virus load and BAL eosinophils and lymphocytes during RV infection. Consistent with our observations of RV-induced asthma exacerbations in humans, infection of mice with allergic airways inflammation increased lung γδT-cell number and activation. Inhibiting γδT-cell responses using anti-γδTCR (anti-γδT-cell receptor) antibody treatment in the mouse asthma exacerbation model increased AHR and airway T helper type 2 cell recruitment and eosinophilia, providing evidence that γδT cells are negative regulators of airways inflammation and disease in RV-induced asthma exacerbations.
10.1038/mi.2013.3
Characterization and function of circulating mucosal-associated invariant T cells and γδT cells in oral lichen planus.
Yang Jing-Ya,Wang Fang,Zhou Gang
Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology
BACKGROUND:Oral lichen planus (OLP) is a T-cell-mediated chronic inflammatory disease with uncertain aetiology. Mucosal-associated invariant T (MAIT) cells and γδT cells are unconventional, innate-like T cells with immunoregulatory capacity. This study aimed to investigate the potential effects of MAIT and γδT cells on the pathogenesis of OLP. METHODS:Circulating MAIT cells and γδT cells were identified using flow cytometry. Surface proteins including CD4, CD8, CD69, CD103, CD49d, programmed death-1 (PD-1) and its ligand PD-L1 were assessed. Cytokines containing interleukin (IL)-4, IL-17, interferon (IFN)-γ, granzyme B and tumour necrosis factor (TNF)-α released by MAIT and γδT cells were measured following PMA and ionomycin stimulation. RESULTS:Circulating MAIT and γδT cells were deficient in OLP. The percentage of CD4 , CD69 , CD103 and PD-1 MAIT cells was increased in OLP, while that of CD8 and CD49d MAIT cells was decreased. The percentage of CD103 , PD-1 and PD-L1 γδT cells was upregulated in OLP. Both the MAIT and γδT cells in OLP produced less IL-4 than controls. The granzyme B-producing MAIT cells were increased, while γδT cells secreting granzyme B and TNF-α were reduced in OLP. IL-17 and IFN-γ in OLP MAIT and γδT cells were not significantly different from that in controls. The frequency of OLP MAIT cells and the MAIT/γδT rate were positively associated with the disease severity. CONCLUSION:The deficient MAIT and γδT cells expressing functional proteins and releasing cytokines may play an immunoregulatory role in the pathogenesis of OLP.
10.1111/jop.13250
Identification of new potential antigen recognized by γδT cells in hepatocellular carcinoma.
Cancer immunology, immunotherapy : CII
In recent years, the application of chimeric antigen receptor T-cell (CAR-T) therapy based on gamma delta T (γδT) cells in hepatocellular carcinoma (HCC) immunotherapy has attracted more and more attention. However, specific antigens recognized by γδT cells are rarely identified, which has become the main restriction on such therapeutic application of γδT cells. In this report, we identified a new peptide and protein antigen recognized by γδT cells in HCC using our previous established strategy. First, we investigated the diversity of the γ9/δ2 T-cell immunorepertoire by sequence analyses of the expressed complementarity-determining region 3 (CDR3) in HCC patients. Then, we constructed γ9/δ2 T-cell receptor (TCR)-transfected cell lines expressing significant HCC CDR3 sequence and identified a series of peptides capable of binding to γδT cells specifically. Next, we identified, further tested and verified the biological functions of these peptides and their matched protein by bioinformatics analysis. We identified that the new protein hepatocyte growth factor-like protein, also called as macrophage-stimulating protein (MSP), and peptide HP1, not only bound to HCC-predominant γδTCR but also effectively activated γδT cells isolated from HCC patients. Moreover, they could stimulate γδT cells in peripheral blood from HCC patients to produce cytokines, which contributed to inhibiting HCC and played an important role in mediating cytotoxicity to HCC cell lines. In conclusion, we identified MSP and HP1, which showed potential as candidates for antigens recognized by γδT cells in HCC.
10.1007/s00262-020-02826-y
IL-17A-producing gammadeltaT cells promote CTL responses against Listeria monocytogenes infection by enhancing dendritic cell cross-presentation.
Xu Sheng,Han Yanmei,Xu Xiongfei,Bao Yan,Zhang Minggang,Cao Xuetao
Journal of immunology (Baltimore, Md. : 1950)
Interleukin-17A-producing T cells, especially Th17, have been shown to be involved in inflammatory autoimmune diseases and host defense against extracellular infections. However, whether and how IL-17A or IL-17A-producing cells can help protection against intracellular bacteria remains controversial, especially how it regulates the adaptive immunity besides recruitment of neutrophils in the innate immune system. By infecting IL-17A-deficient mice with Listeria monocytogenes, we show in this study that IL-17A is required for the generation of Ag-specific CD8(+) CTL response against primary infection, but not for the generation of memory CD8(+) T cells against secondary challenge. Interestingly, we identify γδT cells, but not conventional CD4(+) Th17 cells, as the main cells for innate IL-17A production during L. monocytogenes infection. Furthermore, γδT cells are found to promote Ag-specific CD8(+) T cell proliferation by enhancing cross-presentation of dendritic cells through IL-17A. Adoptive transfer of Il17a(+/+) γδT cells, but not Il17a(-/-) γδT cells or Il17a(+/+) CD4(+) T cells, were sufficient to recover dendritic cells cross-presentation and defective CD8(+) T cell response in Il17a(-/-) mice. Our findings indicate an important role of infection-inducible IL-17A-producing γδT cells and their derived IL-17A against intracellular bacterial infection, providing a mechanism of IL-17A for regulation of innate and adaptive immunity.
10.4049/jimmunol.1001763
Glutamine modulates sepsis-induced changes to intestinal intraepithelial γδT lymphocyte expression in mice.
Lee Wan-Yun,Hu Ya-Mei,Ko Tsui-Ling,Yeh Sung-Ling,Yeh Chiu-Li
Shock (Augusta, Ga.)
This study investigated the effect of glutamine (GLN) on intestinal intraepithelial lymphocyte (IEL) γδT-cell cytokines and immune regulatory factor gene expressions in a mouse model of polymicrobial sepsis. Mice were randomly assigned to a normal group, a sepsis with saline (SS) group, or a sepsis with GLN (SG) group. All mice were fed a chow diet. Sepsis was induced by cecal ligation and puncture (CLP). The SS group was injected with saline, and the SG group was given 0.75 g GLN/kg body weight once via a tail vein 1 h after CLP. Septic mice were killed 12 h after CLP, and IEL γδT cells of the animals were isolated for further analysis. Results showed that compared with normal mice, sepsis resulted in lower IEL γδT-cell percentage and higher messenger RNA expressions of interferon γ, tumor necrosis factor α, interleukin 4 (IL-4), IL-13, IL-17, retinoid acid receptor-related orphan receptor γt, and complement 5a receptor by IEL γδT cells. These immunomodulatory mediator genes exhibited decreases, whereas IL-7 receptor expression increased in IEL γδT cells in septic mice with GLN administration. Annexin V/7-amino-actinomycin D stain revealed significantly lower rates of apoptosis, and IEL γδT-cell percentage was higher in the SG group. The histological findings also showed that damage to intestinal epithelial cells was less severe in the SG group. These results indicated that a single dose of GLN administered as treatment after the initiation of sepsis prevented apoptosis of IEL γδT cells and downregulated γδT cell-expressed inflammatory mediators that may consequently ameliorate the severity of sepsis-induced intestinal epithelial injury.
10.1097/SHK.0b013e3182655932
Development of adoptive immunotherapy with KK-LC-1-specific TCR-transduced γδT cells against lung cancer cells.
Cancer science
The present study analyzed the antitumor effect of γδT cells transduced with the TCR of cancer-specific CTLs to establish forceful cancer-specific adoptive immunotherapy. We cloned the TCRαβ genes from CTLs showing HLA-B15 restricted recognition of Kita-Kyushu lung cancer antigen-1 (KK-LC-1), a cancer/germline gene antigen, identified in a lung adenocarcinoma case (F1121). The TCRαβ and CD8 genes were transduced into γδT cells induced from PBLs of healthy volunteers stimulated with zoledronate and IL-2. The KK-LC-1-specific TCRαβ-CD8 γδT cells showed cytotoxic activity against the KK-LC-1 positive lung cancer cell line F1121L and produced IFN-γ against F1121L and KK-LC-1 peptide-pulsed F1121 EBV-B cells. These responses were blocked by HLA class I and HLA-B/C antibodies. An in vivo assay using NOD/SCID mice with xenotransplantation of human lung cancer cells was performed, and the TCRαβ-CD8 transduced γδT cells (TCRαβ-CD8 γδT cells) were intravenously injected. Growth inhibition of KK-LC-1 , HLA-B15 lung cancer cells was confirmed in mice with injection of the TCRαβ-CD8 γδT cells from 1 wk after xenotransplantation of cancer cells but not in those treated 2 wk after xenotransplantation. The resected specimens of the tumor, 2 wk after xenotransplantation, highly expressed FasL but not programmed death ligand-1 (PD-L1) by immunohistochemical staining. FasL highly expressed cancer cells xenotransplanted 2 wk ago were resistant to TCRαβ-CD8 γδT cells injection. These results suggested that apoptosis of Fas-positive TCRαβ-CD8 γδT cells may be induced by a Fas-mediated signal after interacting with FasL-positive cancer cells.
10.1111/cas.14612
Tissue Resident Memory γδT Cells in Murine Uterus Expressed High Levels of IL-17 Promoting the Invasion of Trophocytes.
Frontiers in immunology
γδT cells are non-conventional T cells and serve as the bridge for connecting the innate and adaptive immune systems. γδT cells form a substantial population at barrier sites and play an important role in the development of physiology, inflammation, autoimmune diseases and tumors. γδT cells not only distribute in the maternal-fetal interface during pregnancy but also in non-pregnant uterus. However, the phenotypes and functions of γδT cells in uterus were not clear. In the current study, we found that the percentages of γδT cells were significantly higher in uterus than peripheral blood and most of γδT cells in uterus were distributed in endometrium. Further studies indicated that the majority of γδT cells in uterus were memory cells with higher expression of CD44 and CD27 but lower expression of CD62L and CCR7 compared to those in blood. In addition, we found that γδT cells in uterus were tissue resident memory γδT cells expressing CD69, expressed high levels of CCR6, GranzymeB and CD107a. Moreover, γδT cells in uterus were activated and fully expressed transcription factor RORγt. After short time of activation, γδT cells in uterus significantly expressed high levels of IL-17 but not IFN-γ, which promotes the invasion of murine trophocytes. Taken together, our study will lay the foundation for future research on uterine γδT cells in pregnancy and autoimmune disease.
10.3389/fimmu.2020.588227
A retrospective cohort study of the impact of peripheral blood gamma- delta T cells to prognosis of nonmetastatic renal cell cancer after curative resection.
Urologic oncology
AIM:Gamma-delta-T cells (γδT) have potential antitumor roles and have recently been applied in adoptive immunotherapy. In the present study, we focused on the proportion of γδT cells in the peripheral blood just before surgery for renal cell cancer (RCC) and investigated whether their proportion affected recurrence-free survival (RFS) and overall survival (OS) retrospectively. PATIENTS AND METHODS:A total of 137 patients with localized, non-metastatic RCC who received surgery at our institutes were analyzed retrospectively. The patients were divided into 2 groups: normal and low γδT cell groups based on the proportion of peripheral blood γδT cells. Kaplan-Meier curves were constructed to access the association of the proportion of peripheral blood γδT cells to RFS and OS. Cox regression were also constructed to access the risks to prognosis. Uni- and multivariate logistic regressions were performed to access associations between risk factors and, RFS and OS. RESULTS:Among 137 patients, 40 had a proportion of γδT cells in peripheral blood of less than 1%, which was below the normal range. The remaining 97 patients had these cells in peripheral blood at 1% or higher. In the groups with low γδT cells, 13 patients had recurrences, and 9 patients dies during the observation period. In the groups with normal γδT cells, 16 patients had recurrences, and 8 patients died. The normal γδT cell group demonstrated significantly better prognosis in terms of RFS and OS. Multivariate analysis revealed that a low hemoglobin level, a low proportion of γδT cells, and a high pathological T stage (pT) were statistically independent risk factors for RFS. Age, albumin, C-reactive protein (CRP), % γδT cells, and pT were statistically significant factors affecting OS and only pT was an independent risk factor by multivariate analysis. CONCLUSION:A low proportion of γδT cells was identified as one of the risk factors for RFS. Our findings will provide clues to develop strategies for early intervention in preventing recurrence even after complete resection of RCC and, such as adoptive immunotherapy using autologous γδT cells in patients with a low proportion of γδT cells.
10.1016/j.urolonc.2023.10.001
Adoptive γδT-cell transfer alone or combined with chemotherapy for the treatment of advanced esophageal cancer.
Sato Yasuyoshi,Mori Kazuhiko,Hirano Kosuke,Yagi Koichi,Kobayashi Yukari,Nagaoka Koji,Hosoi Akihiro,Matsushita Hirokazu,Kakimi Kazuhiro,Seto Yasuyuki
Cytotherapy
BACKGROUND AIMS:After therapy with platinum, 5-fluorouracil and taxane, no further recommended therapy is available for recurrent or metastatic esophageal cancer (r/mEC). Here the authors report two phase 1 trials of adoptive γδT-cell therapy, one for treatment-refractory r/mEC (γδT-monotherapy-P1, UMIN000001419) and the other for r/mEC with no prior systemic therapy (DCF-γδT-P1, UMIN000008097). METHODS:For γδT-monotherapy-P1, patients received four weekly and four biweekly injections of autologous γδT cells. For DCF-γδT-P1, patients received docetaxel, cisplatin and 5-fluorouracil (DCF) chemotherapy consisting of docetaxel (60 mg/m) and cisplatin (60 mg/m) on day 1 and continuous injection of 5-fluorouracil (600 mg/m/day) on days 1-5 of each 28-day cycle; additionally, they received autologous γδT-cell injections on day 15 and day 22 of each cycle. RESULTS:Twenty-six patients were enrolled for γδT-monotherapy-P1. No severe adverse events were associated with γδT-cell therapy. Median overall survival was 5.7 months (95% confidence interval [CI], 4.3-10.0), and median progression-free survival was 2.4 months (95% CI, 1.7-2.8). Eighteen patients received DCF-γδT-P1. All treatment-related adverse events were associated with DCF chemotherapy, not γδT injection. Median overall survival was 13.4 months (95% CI, 6.7-not reached), and median progression-free survival was 4.0 months (95% CI, 2.5-5.7). The response rate and disease control rate were 39% and 78%, respectively. CONCLUSIONS:The use of γδT-cell immunotherapy with or without chemotherapy was safe and feasible for r/mEC patients. Although the authors failed to demonstrate any clinical benefit of γδT-monotherapy-P1, survival benefits were observed in the DCF-γδT-P1 trial.
10.1016/j.jcyt.2021.02.002
"γδT Cell-IL17A-Neutrophil" Axis Drives Immunosuppression and Confers Breast Cancer Resistance to High-Dose Anti-VEGFR2 Therapy.
Zhang Zhigang,Yang Chenghui,Li Lili,Zhu Ying,Su Ke,Zhai Lingyun,Wang Zhen,Huang Jian
Frontiers in immunology
Angiogenesis is an essential physiological process and hallmark of cancer. Currently, antiangiogenic therapy, mostly targeting the vascular endothelial growth factor (VEGF)/VEGFR2 signaling axis, is commonly used in the clinic for solid tumors. However, antiangiogenic therapies for breast cancer patients have produced limited survival benefits since cancer cells rapidly resistant to anti-VEGFR2 therapy. We applied the low-dose and high-dose VEGFR2 mAb or VEGFR2-tyrosine kinase inhibitor (TKI) agents in multiple breast cancer mouse models and found that low-dose VEGFR2 mAb or VEGFR2-TKI achieved good effects in controlling cancer progression, while high-dose treatment was not effective. To further investigate the mechanism involved in regulating the drug resistance, we found that high-dose anti-VEGFR2 treatment elicited IL17A expression in γδ T cells VEGFR1-PI3K-AKT pathway activation and then promoted N2-like neutrophil polarization, thus inducing CD8 T cell exhaustion to shape an immunosuppressive microenvironment. Combining anti-VEGFR2 therapy with immunotherapy such as IL17A, PD-1 or Ly-6G mAb therapy, which targeting the immunomodulatory axis of "γδT17 cells-N2 neutrophils" , showed promising therapeutic effects in breast cancer treatment. This study illustrates the potential mechanism of antiangiogenic therapy resistance in breast cancer and provides synergy treatment for cancer.
10.3389/fimmu.2021.699478
HMGN2: An Antitumor Effector Molecule of γδT Cells.
Chen Jiao,Fan Yaping,Cui Bomiao,Li Xiaoying,Yu Yu,Du Yue,Chen Qianming,Feng Yun,Zhang Ping
Journal of immunotherapy (Hagerstown, Md. : 1997)
γδT cells function in the regulation of T-cell activation in cancer and have been identified as a novel target for cancer immunotherapy. Activated γδT cells release a series of cytotoxic molecules-including granulysin, perforin, Fas/Fas ligand (Fas-L), and granzymes A and B-to kill target cells. Our previous research has shown that high mobility group nucleosomal-binding domain 2 (HMGN2), which is expressed at a high level in activated CD8T cells, is an antitumor effector molecule of CD8T cells. In the present study, we examined the expression and antitumor effects of HMGN2 in γδT cells. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy donors with a PBMC separation column. PMBCs were stimulated with isopentenyl pyrophosphate (IPP) and interleukin-2 (IL-2) for 10 days for activation and expansion. Activated γδT cells were isolated from IPP-pretreated PBMCs with a Moflo XDP flow cytometry sorter. The expression of HMGN2 in γδT cells was detected by flow cytometry and enzyme-linked immunosorbent assay. The cytotoxic effects of γδT cells and HMGN2 were analyzed by carboxyfluorescein succinimidyl ester labeling. IPP combined with IL-2 induced significant activation and expansion of γδT cells in vitro. HMGN2 was constitutively expressed in γδT cells. IPP-activated γδT cells expressed a high level of HMGN2 that could be detected intracellularly and in the supernatant. Moreover, supernatants of purified γδT cells were sufficient to kill tumor cells and could be blocked with anti-human HMGN2 antibody. This study suggests that HMGN2 is an antitumor effector molecule of γδT cells.
10.1097/CJI.0000000000000211
IL12/18/21 Preactivation Enhances the Antitumor Efficacy of Expanded γδT Cells and Overcomes Resistance to Anti-PD-L1 Treatment.
Cancer immunology research
γδT cells are promising candidates for cellular immunotherapy due to their immune regulation through cytokine production and MHC-independent direct cytotoxicity against a broad spectrum of tumors. However, current γδT cell-based cancer immunotherapy has limited efficacy, and novel strategies are needed to improve clinical outcomes. Here, we report that cytokine pretreatment with IL12/18, IL12/15/18, IL12/18/21, and IL12/15/18/21 effectively enhanced the activation and cytotoxicity of in vitro-expanded murine and human γδT cells. However, only adoptive transfer of IL12/18/21 preactivated γδT cells significantly inhibited tumor growth in a murine melanoma model and a hepatocellular carcinoma model. Both IL12/18/21 preactivated antibody-expanded and zoledronate-expanded human γδT cells effectively controlled tumor growth in a humanized mouse model. IL12/18/21 preactivation promoted γδT cell proliferation and cytokine production in vivo and enhanced IFNγ production and activation of endogenous CD8+ T cells in a cell-cell contact- and ICAM-1-dependent manner. Furthermore, the adoptive transfer of IL12/18/21 preactivated γδT cells could overcome the resistance to anti-PD-L1 therapy, and the combination therapy had a synergistic effect on the therapeutic outcomes. Moreover, the enhanced antitumor function of adoptively transferred IL12/18/21 preactivated γδT cells was largely diminished in the absence of endogenous CD8+ T cells when administered alone or in combination with anti-PD-L1, suggesting a CD8+ T cell-dependent mechanism. Taken together, IL12/18/21 preactivation can promote γδT cell antitumor function and overcome the resistance to checkpoint blockade therapy, indicating an effective combinational cancer immunotherapeutic strategy.
10.1158/2326-6066.CIR-21-0952
The function of MSP-activated γδT cells in hepatocellular carcinoma.
International immunopharmacology
Immunotherapeutic strategies targeting γδT cells are now recognized as a promising treatment method for hepatocellular carcinoma (HCC). To date, no specific antigen or antigenic epitope recognized by γδT cells has been identified, limiting their application in the field of HCC treatment. Previously, we used an established screening strategy to identify a novel HCC protein antigen recognized by γδT cells called MSP. In this study, we explored the function of MSP activated-γδT cells in HCC. Results demonstrated that the proportions of γδT cells in the peripheral blood of HCC patients and the level of IFN-γ in the serum were higher than in healthy controls. We also determined that γδT cells can bind MSP protein. MSP-activated γδT cells were shown to contain a specific CDR3δ2 sequence that supports the recognition of MSP by γδT cells. We determined that MSP is highly expressed in HCC, MSP-activated γδT cells in the peripheral blood of HCC patients express co-stimulatory molecules, and MSP-activated γδT cells directly killed HCC cells. In conclusion, we demonstrated that the novel protein ligand MSP activated γδT cells, leading to the killing of HCC cells through direct and indirect mechanisms. These findings could provide a potential new target for the clinical diagnosis and treatment of HCC and a foundation for clinical treatment strategies in HCC.
10.1016/j.intimp.2023.110893
Localized ablative immunotherapy enhances antitumor immunity by modulating the transcriptome of tumor-infiltrating Gamma delta T cells.
Cancer letters
Gamma delta T cells (γδT cells) play crucial roles in the immune response against tumors, yet their functional dynamics under different cancer therapies remain poorly understood. Laser Ablative Immunotherapy (LAIT) is a novel cancer treatment modality combining local photothermal therapy (PTT) and intratumoral injection of an immunostimulant, N-dihydrogalactochitosan (glycated chitosan, GC). LAIT has been shown to induce systemic antitumor immune responses in pre-clinical studies and clinical trials, eradicating both treated local tumors and untreated distant metastases. In this study, we used LAIT to treat breast tumors in a mouse model and investigated the effects of LAIT on tumor-infiltrating γδT cells using single-cell RNA sequencing (scRNAseq). We characterized the γδT cells from tumors in control, PTT, GC, and LAIT (PTT + GC) groups, by identifying six distinct subtypes: activated, cytotoxic, cycling cytotoxic, IFN-enriched, antigen-presenting, and IL17-producing γδT cells. Differential gene expression analysis revealed that LAIT significantly upregulated genes associated with T cell activation, leukocyte adhesion, and interferon signaling in treated tumor tissues while downregulating genes involved in protein folding and stress responses. LAIT also uniquely increased the proportion of IL17-producing γδT cells, which correlated with prolonged survival in breast cancer patients, as analyzed using TCGA data. Furthermore, the transcriptomic profiles of γδT cells in LAIT-treated tumors closely resembled those in immune checkpoint inhibitor (ICI)-treated patients, suggesting potential synergistic effects. Our findings indicate that LAIT modulates the γδT cell transcriptome, enhancing their antitumor capabilities and providing a basis for combining LAIT with ICI therapy to improve cancer treatment outcomes.
10.1016/j.canlet.2024.217267
γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation.
Cell
Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated γδT cell population, which constituted ∼40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of γδT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of γδT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of αβT cells. Although αβT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon γδT cell ablation. PDA-infiltrating γδT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in γδT cells enhanced CD4(+) and CD8(+) T cell infiltration and immunogenicity and induced tumor protection suggesting that γδT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe γδT cells as central regulators of effector T cell activation in cancer via novel cross-talk.
10.1016/j.cell.2016.07.046
L-theanine intervention enhances human gammadeltaT lymphocyte function.
Bukowski Jack F,Percival Susan S
Nutrition reviews
Human gammadeltaT lymphocytes are a subset of T cells and are a first line of defense against microbes and tumors. These gammadeltaT cells can be primed by nitrogen-containing bisphosphonates, and certain short-chain alkylamines. These primed gammadeltaT cells have an enhanced capacity to proliferate and to secrete cytokines upon ex vivo exposure to a wide variety of microbes and tumor cells. The largest dietary source of alkylamines is L-theanine, an amino acid unique to tea beverages that is catabolized to ethylamine. Supplementation of subjects with capsules containing L-theanine and catechins has recently been shown to decrease the incidence of cold and flu symptoms, while enhancing gammadeltaT cell function.
10.1111/j.1753-4887.2007.00013.x
Targeting Cytokine Signals to Enhance γδT Cell-Based Cancer Immunotherapy.
Frontiers in immunology
γδT cells represent a small percentage of T cells in circulation but are found in large numbers in certain organs. They are considered to be innate immune cells that can exert cytotoxic functions on target cells without MHC restriction. Moreover, γδT cells contribute to adaptive immune response regulating other immune cells. Under the influence of cytokines, γδT cells can be polarized to different subsets in the tumor microenvironment. In this review, we aimed to summarize the current understanding of antigen recognition by γδT cells, and the immune regulation mediated by γδT cells in the tumor microenvironment. More importantly, we depicted the polarization and plasticity of γδT cells in the presence of different cytokines and their combinations, which provided the basis for γδT cell-based cancer immunotherapy targeting cytokine signals.
10.3389/fimmu.2022.914839
mRNA-Engineered CD5-CAR-γδT Cells for the Immunotherapy of T-Cell Acute Lymphoblastic Leukemia.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
Clinical trials of Chimeric Antigen Receptor T-cell (CAR-T) therapy have demonstrated remarkable success in treating both solid tumors and hematological malignancies. Nanobodies (Nbs) have emerged as promising antigen-targeting domains for CARs, owing to their high specificity, robust stability, and strong affinity, leading to significant advancements in the field of Nb-CAR-T. In the realm of T-cell acute lymphoblastic leukemia (T-ALL) targets, CD5 stands out as a potentially excellent candidate for T-cell-based CAR therapy, due to its distinct expression on the surface of malignant T-ALL cells. To mitigate graft-versus-host disease associated with allogeneic CAR-T, γδT cells are selected and stimulated from peripheral blood mononuclear cells, and γδT cells are engineered via CRISPR/Cas9 to eliminate fratricide, enabling the creation of fratricide-resistant CAR-γδT cells. In vitro transcribed (IVT) mRNA is used to construct CAR-T, presenting a safer, faster, and cost-effective method compared to traditional viral vector approaches. In this study, a CD5-VHH library is constructed, and specific CD5-nanobodies are screened for subsequent use in CD5-CAR-γδT therapy. IVT-mRNA-CD5-CAR-γδT cells exhibited favorable functional characteristics and demonstrated antitumor efficacy against malignant T cell lines, underlining the potential for advancing mRNA-CD5-CAR-γδT therapy.
10.1002/advs.202400024