Anti-KIT Monoclonal Antibody Treatment Enhances the Antitumor Activity of Immune Checkpoint Inhibitors by Reversing Tumor-Induced Immunosuppression.
Garton Andrew J,Seibel Scott,Lopresti-Morrow Lori,Crew Linda,Janson Neal,Mandiyan Sreekala,Trombetta E Sergio,Pankratz Shannon,LaVallee Theresa M,Gedrich Richard
Molecular cancer therapeutics
The receptor tyrosine kinase KIT is an established oncogenic driver of tumor growth in certain tumor types, including gastrointestinal stromal tumors, in which constitutively active mutant forms of KIT represent an actionable target for small-molecule tyrosine kinase inhibitors. There is also considerable potential for KIT to influence tumor growth indirectly based on its expression and function in cell types of the innate immune system, most notably mast cells. We have evaluated syngeneic mouse tumor models for antitumor effects of an inhibitory KIT mAb, dosed either alone or in combination with immune checkpoint inhibitors. Anti-KIT mAb treatment enhanced the antitumor activity of anti-CTLA-4 and anti-PD-1 mAbs, and promoted immune responses by selectively reducing the immunosuppressive monocytic myeloid-derived suppressor cell population and by restoring CD8 and CD4 T-cell populations to levels observed in naïve mice. These data provide a rationale for clinical investigation of the human KIT-specific mAb KTN0158 in novel immuno-oncology combinations with immune checkpoint inhibitors and other immunotherapeutic agents across a range of tumor types. .
Tumor infiltrating lymphocytes: The regulator of melanoma evolution.
Antohe Mihaela,Nedelcu Roxana Ioana,Nichita Luciana,Popp Cristiana Gabriela,Cioplea Mirela,Brinzea Alice,Hodorogea Anastasia,Calinescu Andreea,Balaban Mihaela,Ion Daniela Adriana,Diaconu Carmen,Bleotu Coralia,Pirici Daniel,Zurac Sabina Andrada,Turcu Gabriela
Melanoma is the most severe type of skin cancer and its incidence has increased in the last decades. In the United States, it is the 6th most common cancer in both men and women. Prognosis for patients with melanoma depends on the stage of the disease at the time of diagnosis and it can be influenced by the immunologic response. Melanoma has been historically considered an immunogenic malignancy. It often contains great amount of immune cells (different subsets of T-cells, dendritic cells, macrophages, neutrophils, mast cells, B lymphocytes), which may reflect a continuous intercommunication between host and tumor. It is not established if tumor-infiltrating lymphocytes (TILs) are induced by tumor cells or by other components of the microenvironment or when they are a host direct immunologic reaction. It has been observed that in many cases, the presence of a dense TIL is associated with good prognosis. The pattern and activation state of the cells which constitute TIL is variable and modulates the clinical outcome. An important step in the understanding of tumor immunobiology is the analysis of the populations and subsets of immune cells that form TIL. Besides its prognostic significance, after approval of cytotoxic T lymphocyte antigen 4, programmed cell death-1 and programmed death-1 ligand antibodies for the treatment of melanoma, the assessment of immune infiltrate composition has become even more captivating, as it could provide new target molecules and new biomarkers for predicting the effect of the treatment and disease outcome in patients treated with immunotherapy. In this review we discuss current state of knowledge in the field of immune cells that infiltrate melanoma, resuming the potential of TIL components to become prognostic markers for natural evolution, for response to drugs or valuable targets for new medication.
New insights into the interaction of the immune system with non-small cell lung carcinomas.
Translational lung cancer research
The basis of current and future lung cancer immunotherapy depends mainly on our knowledge of the molecular mechanisms of interactions between cancer and immune cells (ICs), as well as on interactions occurring between the different populations of intra-tumor ICs. These interactions are very complex, as virtually all immune cell types, including macrophages, neutrophils, mast cells, natural killer (NK) cells, dendritic cells and T and B lymphocytes can infiltrate lung cancer tissues at the same time. Moreover these interactions lead to progressive emergence of an imbalance in ICs. Initially ICs have an anti-tumor effect but then induce immune tolerance and eventually tumor progression and dissemination. All the cells of innate and adaptive intra-tumor immunity engage in this progressive phenotypic switch. A majority of non-small cell lung carcinoma (NSCLC) patients do not benefit from the expected positive responses associated with current immunotherapy. Thus, there is urgent need to better understand the different roles of the associated cancer ICs. This review summarizes some of the new insights into this domain, with particular focus on: the myeloid cell population associated with tumors, the tertiary lymphoid structures (TLSs), the role of the P2 purinergic receptors (P2R) and ATP, and the new concept of the "liquid microenvironment" implying blood circulating ICs.
CXCL12 and CD3E as Indicators for Tumor Microenvironment Modulation in Bladder Cancer and Their Correlations With Immune Infiltration and Molecular Subtypes.
Liu Yi,Wu YuCai,Zhang PeiPei,Xu ChaoJie,Liu ZeSen,He ChaoJie,Liu YiMing,Kang ZhengJun
Frontiers in oncology
Bladder cancer (BLCA) represents the ninth most common malignant tumor in the world and is characterized by high recurrence risk. Tumor microenvironment (TME) plays an important role in regulating the progression of BLCA. Immunotherapy, including Bacillus Calmette-Guerin (BCG) and programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1), is closely associated with TME and is widely used for treating BLCA. But parts of BLCA patients have no response to these treatment ways, thus a better understanding of the complex TME of BLCA is still needed. We downloaded the gene expression profile and corresponding clinical information of 414 BLCA patients from the TCGA database. the ESTIMATE and CIBERSORT algorithm, we identified the two hub genes (CXCL12 and CD3E) and explored their correlations with immune infiltration. We found that BLCA patients with higher expression of CXCL12 and lower expression of CD3E had prolonged survival. Gene set enrichment analysis (GSEA) revealed that both CXCL12 and CD3E were enriched in immune-related pathways. We also discovered that stromal score and the level of CXCL12 were higher in luminal subtype, and immune score and the level of CD3E were higher in the basal subtype. Furtherly, we found that CXCL12 was associated with naive B cells, resting mast cell, M2 macrophages, follicular helper T cells, and dendritic cells. CD8 T cells, CD4 T cells, regulatory T cells (Tregs), and macrophages were correlated with CD3E. In conclusions, we found that CXCL12 and CD3E might serve as indicators of TME modulation in BLCA. Therapy targeting CXCL12 and CD3E had the potential as novel therapeutic strategy.
Overview of Basic Immunology and Clinical Application.
Stephen Bettzy,Hajjar Joud
Advances in experimental medicine and biology
Tumor exists as a complex network of structures with an ability to evolve and evade the host immune surveillance mechanism. The immune milieu which includes macrophages, dendritic cells, natural killer cells, neutrophils, mast cells, B cells, and T cells are found in the core, the invasive margin, or the adjacent stromal or lymphoid component of the tumor. The immune infiltrate is heterogeneous and varies within a patient and between patients of the same tumor histology. The location, density, functionality, and cross-talk between the immune cells in the tumor microenvironment influence the nature of immune response, prognosis, and treatment outcomes in cancer patients. Therefore, an understanding of the characteristics of the immune cells and their role in tumor immune surveillance is of paramount importance to identify immune targets and to develop novel immune therapeutics in the war against cancer. In this chapter, we provide an overview of the individual components of the human immune system and the translational relevance of predictive biomarkers.
Friend or Foe: Prognostic and Immunotherapy Roles of BTLA in Colorectal Cancer.
Song Jingjing,Wu Lihui
Frontiers in molecular biosciences
Background:B and T lymphocyte attenuator (BTLA) is a co-signaling protein belonging to the CD28 immunoglobulin superfamily. However, the role of BTLA in prognosis and immunotherapy of colorectal cancer (CRC) remains unclear. Methods:We evaluated the expression of BTLA via the Oncomine and the cancer genome atlas (TCGA) database. We research the outcome among different BTLA expression patients by Kaplan-Meier curve. We used the Chi-Squared test and Cox regression analysis to identify potential risk factors. Besides, the correlations between BTLA and cancer immune infiltration were investigated via CIBERSORT. Results:Various cohorts showed that BTLA expression was lower in CRC compared to corresponding normal tissue. Moreover, low BTLA expression was correlated with poor overall survival in TCGA cohorts and Gene Expression Omnibus cohorts (GSE29623 and GSE17536). Low BTLA expression was associated with less lymph node metastasis ( = 0.0123). In the Cox proportional hazards model, BTLA was identified as a favorable prognostic factor. Naive B cells, memory B cells, CD8 T cells, CD4 memory resting T cells, follicular helper T (Tfh) cells, monocytes, resting natural killing (NK) cells, M0 macrophages, M1 macrophages, resting mast cells, and activated mast cells were affected by BTLA expression (all < 0.01). Correlated immune markers and functional enrichment analysis revealed BTLA functioned in the T cell receptor signaling pathway, B cell receptor signaling pathway, and NK cell-mediated cytotoxicity pathway. Conclusion:These analyses suggest BTLA is a potential factor for extended survival and closely related to CD8 T cells, Tfh cells, B cells, and NK cells in CRC. We summarize these results that BTLA can be used as a prognostic biomarker and might contribute to developing novel CRC immunological treatment strategies.
Myeloid cell heterogeneity in lung cancer: implication for immunotherapy.
Sangaletti Sabina,Ferrara Roberto,Tripodo Claudio,Garassino Marina Chiara,Colombo Mario Paolo
Cancer immunology, immunotherapy : CII
Lung is a specialized tissue where metastases from primary lung tumors takeoff and those originating from extra-pulmonary sites land. One commonality characterizing these processes is the supportive role exerted by myeloid cells, particularly neutrophils, whose recruitment is facilitated in this tissue microenvironment. Indeed, neutrophils have important part in the pathophysiology of this organ and the key mechanisms regulating neutrophil expansion and recruitment during infection can be co-opted by tumor cells to promote growth and metastasis. Although neutrophils dominate the myeloid landscape of lung cancer other populations including macrophages, dendritic cells, mast cells, basophils and eosinophils contribute to the complexity of lung cancer TME. In this review, we discuss the origin and significance of myeloid cells heterogeneity in lung cancer, which translates not only in a different frequency of immune populations but it encompasses state of activation, morphology, localization and mutual interactions. The relevance of such heterogeneity is considered in the context of tumor growth and response to immunotherapy.
Tumor microenvironment-associated gene C3 can predict the prognosis of colorectal adenocarcinoma: a study based on TCGA.
Liu Y,Wang X
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico
BACKGROUND:Colorectal cancer is one of the most common malignancies. With continuous exploration of the interaction between tumor cells and the immune system, tumor immunotherapy has become a revolution. However, CRC remains one of the less effective tumors for immunotherapy. The tumor microenvironment plays an important role in tumorigenesis and progression. The aim of this study is to explore tumor microenvironment-related genes that can predict the prognosis of colorectal adenocarcinoma, and also to provide new ideas for the mechanism of tumor development as well as immunotherapy. METHODS:After estimating Stromalscore and Immunescore of colorectal adenocarcinoma tumor samples according to RNA-Seq expression data downloaded from TCGA, we screened for TME-related differential genes. We filtered prognosis-related core genes by constructing protein-protein interaction networks and making one-factor cox analysis for prognosis. Finally, the relative content of 22 immune cells in tumor tissues was evaluated, and then immune cells associated with core genes were identified. RESULTS:We screened 773 differential genes related to the TME. Then we identified C3 as a core gene associated with prognosis. Single gene analysis showed that C3 expression was significantly higher in tumor tissues than in normal tissues (p < 0.001). High C3 expression was associated with lower overall survival (p = 0.046). Tumor immune cell analysis showed that mast cells resting, mast cells activated, T cells CD4 memory activated, eosinophils, and macrophages M0 were C3-associated immune cells. CONCLUSIONS:C3 has potential as a biomarker for colorectal adenocarcinoma and could provide new research ideas for the diagnosis and treatment of colorectal adenocarcinoma, especially for immunotherapy.
Immunotherapy for cancer: promoting innate immunity.
Lotfi Ramin,Schrezenmeier Hubert,Lotze Michael Thomas
Frontiers in bioscience (Landmark edition)
Development of tumor over many years leads to reciprocal alterations in the host immune response and the tumor, enabling tumor growth seemingly paradoxically in the setting of necrosis and inflammation. Innate immune cells, granulocytes - neutrophils, eosinophils, basophils - and mast cells belong to the first line of defense sensing pathogen and damage associated molecular pattern (PAMPs, DAMPs) signals, initiating and modulating the subsequent inflammatory response. Nontheless, the prevailing contemporary strategies of immunotherapy for cancer have focused on the second line of the immune response, the adaptive immune response. We have determined that most highly evolved tumors in adults undergo necrosis, releasing DAMPs, promoting reactive angiogenesis, stromagenesis and reparative epithelial proliferation of the tumor cell. Means to aerobically eliminate such DAMPs by peroxidases released by innate immune effectors allows us to consider novel strategies for limiting tumor progression. Summarized here is our current understanding of acute and chronic inflammation and its impact on tumor development, the pathophysiology of immunity in cancer, and the influence of granulocytes and mast cells in this setting.
Immune signature of tumor-infiltrating immune cells predicts the prognosis and therapeutic effects in squamous cell carcinoma.
Che Yun,Luo Zhiwen,Zhang Chaoqi,Sun Nan,Gao Shugeng,He Jie
Tumor-infiltrating immune cells (TICs) are involved in tumor progression and determine the prognosis. We investigated how TICs affect the prognosis and therapeutic effects of squamous cell carcinoma (SCC), which share common histological features and certain risk factors. The SCC data from The Cancer Genome Atlas (TCGA) and Gene expression Omnibus (GEO) databases were downloaded to evaluate the composition of TICs with the CIBERSORT algorithm. LASSO and Cox multivariate regression analyses were used to build a prognostic risk model. Chemotherapeutic and immunotherapeutic responses were compared between patients with SCC. A Gene set variation analysis (GSVA) was also performed to elucidate the mechanism. Naïve B cells and resting mast cells were selected to construct the prognostic model. According to these two immune cell subtypes, patients with SCC were divided into low- and high-risk groups. The low-risk group with high proportions of naïve B cells and resting mast cells had a better overall survival rate than the high-risk group and might benefit from immunotherapy and chemotherapy due to differences in the immune microenvironment. Activation of the Wnt signaling pathway was observed in the high-risk group. Based on the findings from the present study, the immune signature provides prognostic determinants of SCC and may be a biomarker to guide chemotherapy and immunotherapy. Wnt inhibitors may be attractive candidates for combination treatment in high-risk patients with SCC.
The Crosstalk Between Tumor Cells and the Immune Microenvironment in Breast Cancer: Implications for Immunotherapy.
Salemme Vincenzo,Centonze Giorgia,Cavallo Federica,Defilippi Paola,Conti Laura
Frontiers in oncology
Breast cancer progression is a complex process controlled by genetic and epigenetic factors that coordinate the crosstalk between tumor cells and the components of tumor microenvironment (TME). Among those, the immune cells play a dual role during cancer onset and progression, as they can protect from tumor progression by killing immunogenic neoplastic cells, but in the meanwhile can also shape tumor immunogenicity, contributing to tumor escape. The complex interplay between cancer and the immune TME influences the outcome of immunotherapy and of many other anti-cancer therapies. Herein, we present an updated view of the pro- and anti-tumor activities of the main immune cell populations present in breast TME, such as T and NK cells, myeloid cells, innate lymphoid cells, mast cells and eosinophils, and of the underlying cytokine-, cell-cell contact- and microvesicle-based mechanisms. Moreover, current and novel therapeutic options that can revert the immunosuppressive activity of breast TME will be discussed. To this end, clinical trials assessing the efficacy of CAR-T and CAR-NK cells, cancer vaccination, immunogenic cell death-inducing chemotherapy, DNA methyl transferase and histone deacetylase inhibitors, cytokines or their inhibitors and other immunotherapies in breast cancer patients will be reviewed. The knowledge of the complex interplay that elapses between tumor and immune cells, and of the experimental therapies targeting it, would help to develop new combination treatments able to overcome tumor immune evasion mechanisms and optimize clinical benefit of current immunotherapies.
Targeting KIT on innate immune cells to enhance the antitumor activity of checkpoint inhibitors.
Stahl Maximilian,Gedrich Richard,Peck Ronald,LaVallee Theresa,Eder Joseph Paul
Innate immune cells such as mast cells and myeloid-derived suppressor cells are key components of the tumor microenvironment. Recent evidence indicates that levels of myeloid-derived suppressor cells in melanoma patients are associated with poor survival to checkpoint inhibitors. This suggests that targeting both the innate and adaptive suppressive components of the immune system will maximize clinical benefit and elicit more durable responses in cancer patients. Preclinical data suggest that targeting signaling by the receptor tyrosine kinase KIT, particularly on mast cells, may modulate innate immune cell numbers and activity in tumors. Here, we review data highlighting the importance of the KIT signaling in regulating antitumor immune responses and the potential benefit of combining selective KIT inhibitors with immune checkpoint inhibitors.
Contribution to Tumor Angiogenesis From Innate Immune Cells Within the Tumor Microenvironment: Implications for Immunotherapy.
Albini Adriana,Bruno Antonino,Noonan Douglas M,Mortara Lorenzo
Frontiers in immunology
The critical role of angiogenesis in promoting tumor growth and metastasis is strongly established. However, tumors show considerable variation in angiogenic characteristics and in their sensitivity to antiangiogenic therapy. Tumor angiogenesis involves not only cancer cells but also various tumor-associated leukocytes (TALs) and stromal cells. TALs produce chemokines, cytokines, proteases, structural proteins, and microvescicles. Vascular endothelial growth factor (VEGF) and inflammatory chemokines are not only major proangiogenic factors but are also immune modulators, which increase angiogenesis and lead to immune suppression. In our review, we discuss the regulation of angiogenesis by innate immune cells in the tumor microenvironment, specific features, and roles of major players: macrophages, neutrophils, myeloid-derived suppressor and dendritic cells, mast cells, γδT cells, innate lymphoid cells, and natural killer cells. Anti-VEGF or anti-inflammatory drugs could balance an immunosuppressive microenvironment to an immune permissive one. Anti-VEGF as well as anti-inflammatory drugs could therefore represent partners for combinations with immune checkpoint inhibitors, enhancing the effects of immune therapy.
The roles of mast cells in anticancer immunity.
Dalton Dyana K,Noelle Randolph J
Cancer immunology, immunotherapy : CII
The tumor microenvironment (TME), which is composed of stromal cells such as endothelial cells, fibroblasts, and immune cells, provides a supportive niche promoting the growth and invasion of tumors. The TME also raises an immunosuppressive barrier to effective antitumor immune responses and is therefore emerging as a target for cancer immunotherapies. Mast cells (MCs) accumulate in the TME at early stages, and their presence in the TME is associated with poor prognosis in many aggressive human cancers. Some well-established roles of MCs in cancer are promoting angiogenesis and tumor invasion into surrounding tissues. Several mouse models of inducible and spontaneous cancer show that MCs are among the first immune cells to accumulate within and shape the TME. Although MCs and other suppressive myeloid cells are associated with poor prognosis in human cancers, high densities of intratumoral T effector (T(eff)) cells are associated with a favorable prognosis. The latter finding has stimulated interest in developing therapies to increase intratumoral T cell density. However, cellular and molecular mechanisms promoting high densities of intratumoral T(eff) cells within the TME are poorly understood. New evidence suggests that MCs are essential for shaping the immune-suppressive TME and impairing both antitumor T(eff) cell responses and intratumoral T cell accumulation. These roles for MCs warrant further elucidation in order to improve antitumor immunity. Here, we will summarize clinical studies of the prognostic significance of MCs within the TME in human cancers, as well as studies in mouse models of cancer that reveal how MCs are recruited to the TME and how MCs facilitate tumor growth. Also, we will summarize our recent studies indicating that MCs impair generation of protective antitumor T cell responses and accumulation of intratumoral T(eff) cells. We will also highlight some approaches to target MCs in the TME in order to unleash antitumor cytotoxicity.
Mast Cells as Drivers of Disease and Therapeutic Targets.
Siebenhaar Frank,Redegeld Frank A,Bischoff Stephan C,Gibbs Bernhard F,Maurer Marcus
Trends in immunology
Mast cells (MCs) contribute to the pathogenesis of a multitude of diseases that include MC-driven disorders such as urticaria, type I allergies, and mastocytosis as well as autoimmune and other inflammatory disorders and malignant tumors. Here, we review and discuss the results of studies that identified and characterized how MCs contribute to disease and, importantly, what strategies may be used to target MCs and MC effects therapeutically. Specifically, we discuss the most common approaches for investigating the role and relevance of MCs in various diseases. We also review current therapeutic approaches aimed at modulating MC numbers, inhibiting MCs and/or preventing MC activation, modulating MC signal transduction and protection from the effects of MC mediators.
Human Mast Cells From Adipose Tissue Target and Induce Apoptosis of Breast Cancer Cells.
Plotkin Jesse D,Elias Michael G,Fereydouni Mohammad,Daniels-Wells Tracy R,Dellinger Anthony L,Penichet Manuel L,Kepley Christopher L
Frontiers in immunology
Mast cells (MC) are important immune sentinels found in most tissue and widely recognized for their role as mediators of Type I hypersensitivity. However, they also secrete anti-cancer mediators such as tumor necrosis factor alpha (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The purpose of this study was to investigate adipose tissue as a new source of MC in quantities that could be used to study MC biology focusing on their ability to bind to and kill breast cancer cells. We tested several cell culture media previously demonstrated to induce MC differentiation. We report here the generation of functional human MC from adipose tissue. The adipose-derived mast cells (ADMC) are phenotypically and functionally similar to connective tissue expressing tryptase, chymase, c-kit, and FcεRI and capable of degranulating after cross-linking of FcεRI. The ADMC, sensitized with anti-HER2/ IgE antibodies with human constant regions (trastuzumab IgE and/or C6MH3-B1 IgE), bound to and released MC mediators when incubated with HER2/-positive human breast cancer cells (SK-BR-3 and BT-474). Importantly, the HER2/ IgE-sensitized ADMC induced breast cancer cell (SK-BR-3) death through apoptosis. Breast cancer cell apoptosis was observed after the addition of cell-free supernatants containing mediators released from FcεRI-challenged ADMC. Apoptosis was significantly reduced when TNF-α blocking antibodies were added to the media. Adipose tissue represents a source MC that could be used for multiple research purposes and potentially as a cell-mediated cancer immunotherapy through the expansion of autologous (or allogeneic) MC that can be targeted to tumors through IgE antibodies recognizing tumor specific antigens.
Mast-Cell-Derived TNF Amplifies CD8(+) Dendritic Cell Functionality and CD8(+) T Cell Priming.
Dudeck Jan,Ghouse Shanawaz Mohammed,Lehmann Christian H K,Hoppe Anja,Schubert Nadja,Nedospasov Sergei A,Dudziak Diana,Dudeck Anne
Mast cells are critical promoters of adaptive immunity in the contact hypersensitivity model, but the mechanism of allergen sensitization is poorly understood. Using Mcpt5-CreTNF(FL/FL) mice, we show here that the absence of TNF exclusively in mast cells impaired the expansion of CD8(+) T cells upon sensitization and the T-cell-driven adaptive immune response to elicitation. T cells primed in the absence of mast cell TNF exhibited a diminished efficiency to transfer sensitization to naive recipients. Specifically, mast cell TNF promotes CD8(+) dendritic cell (DC) maturation and migration to draining lymph nodes. The peripherally released mast cell TNF further critically boosts the CD8(+) T-cell-priming efficiency of CD8(+) DCs, thereby linking mast cell effects on T cells to DC modulation. Collectively, our findings identify the distinct potential of mast cell TNF to amplify CD8(+) DC functionality and CD8(+) T-cell-dominated adaptive immunity, which may be of great importance for immunotherapy and vaccination approaches.
IL33 and Mast Cells-The Key Regulators of Immune Responses in Gastrointestinal Cancers?
Eissmann Moritz F,Buchert Michael,Ernst Matthias
Frontiers in immunology
The Interleukin (IL-)1 family IL33 is best known for eliciting type 2 immune responses by stimulating mast cells (MCs), regulatory T-cells (Tregs), innate lymphoid cells (ILCs) and other immune cells. MCs and IL33 provide critical control of immunological and epithelial homeostasis in the gastrointestinal (GI) tract. Meanwhile, the role of MCs in solid malignancies appears tissue-specific with both pro and anti-tumorigenic activities. Likewise, IL33 signaling significantly shapes immune responses in the tumor microenvironment, but these effects remain often dichotomous when assessed in experimental models of cancer. Thus, the balance between tumor suppressing and tumor promoting activities of IL33 are highly context dependent, and most likely dictated by the mixture of cell types responding to IL33. Adding to this complexity is the promiscuous nature by which MCs respond to cytokines other than IL33 and release chemotactic factors that recruit immune cells into the tumor microenvironment. In this review, we integrate the outcomes of recent studies on the role of MCs and IL33 in cancer with our own observations in the GI tract. We propose a working model where the most abundant IL33 responsive immune cell type is likely to dictate an overall tumor-supporting or tumor suppressing outcome . We discuss how these opposing responses affect the therapeutic potential of targeting MC and IL33, and highlight the caveats and challenges facing our ability to effectively harness MCs and IL33 biology for anti-cancer immunotherapy.
Mast cells: A double-edged sword in cancer.
Derakhshani Afshin,Vahidian Fatemeh,Alihasanzadeh Mohammad,Mokhtarzadeh Ahad,Lotfi Nezhad Parisa,Baradaran Behzad
Mast cells (MCs), a type of innate immune cells, are derived from myeloid stem cells, sometimes known as mastocytes or labrocytes, and contain many granules rich in histamine and heparin. The mentioned cells are able to release various mediators such as cytokines, leukotrienes, and a large number of proteases into the environment. Many studies and experiments have established the infiltration of MCs into the tumor site. However, the findings are highly controversial to determine whether these immune cells contribute to the growth and development of the tumor or cause anti-tumor immune responses. Various studies have revealed that MCs have a pro-tumorigenic or anti-tumorigenic role depending on the type of cancer, the degree of tumor progression, and the location of these immune cells in the tumor bulk. Although these types of immune cells cause angiogenesis and tumor progression in some cancers, they have a significant anti-tumor role in some other types of cancers. In general, although a number of studies have specified the protective role of MCs in cancers, the increased number of MCs in the blood and microenvironment of tumors, as well as the increased level of angiogenesis and tumor progression, has been indicated in another array of studies. The function of MCs against or in favor of the cancers still requires further investigations to more accurately and specifically determine the role of MCs in the cancers. The function of MCs in tumors and their various roles in case of exposure to the cancer cells have been addressed in the present review. The concluding section of the present study recommends a number of methods for modification of MCs in cancer immunotherapy.
A critical role for mast cells and mast cell-derived IL-6 in TLR2-mediated inhibition of tumor growth.
Oldford Sharon A,Haidl Ian D,Howatt Mackenzie A,Leiva Carlos A,Johnston Brent,Marshall Jean S
Journal of immunology (Baltimore, Md. : 1950)
Several TLR agonists are effective in tumor immunotherapy, but their early innate mechanisms of action, particularly those of TLR2 agonists, are unclear. Mast cells are abundant surrounding solid tumors where they are often protumorigenic and enhance tumor angiogenesis. However, antitumor roles for mast cells have also been documented. The impact of mast cells may be dependent on their activation status and mediator release in different tumors. Using an orthotopic melanoma model in wild-type C57BL/6 and mast cell-deficient Kit(W-sh/W-sh) mice and a complementary Matrigel-tumor model in C57BL/6 mice, mast cells were shown to be crucial for TLR2 agonist (Pam(3)CSK(4))-induced tumor inhibition. Activation of TLR2 on mast cells reversed their well-documented protumorigenic role. Tumor growth inhibition after peritumoral administration of Pam(3)CSK(4) was restored in Kit(W-sh/W-sh) mice by local reconstitution with wild-type, but not TLR2-deficient, mast cells. Mast cells secrete multiple mediators after Pam(3)CSK(4) activation, and in vivo mast cell reconstitution studies also revealed that tumor growth inhibition required mast cell-derived IL-6, but not TNF. Mast cell-mediated anticancer properties were multifaceted. Direct antitumor effects in vitro and decreased angiogenesis and recruitment of NK and T cells in vivo were observed. TLR2-activated mast cells also inhibited the growth of lung cancer cells in vivo. Unlike other immune cells, mast cells are relatively radioresistant making them attractive candidates for combined treatment modalities. This study has important implications for the design of immunotherapeutic strategies and reveals, to our knowledge, a novel mechanism of action for TLR2 agonists in vivo.
Interaction between regulatory T cells and mast cells via IL-9 and TGF-β production.
Zhao Yi-Bin,Yang Shao-Hui,Shen Jie,Deng Ke,Li Qi,Wang Yu,Cui Wei,Ye Hua
Research on the immunosuppression of cancer cells has attracted much attention in recent years. The present study sought to provide a new strategy for tumor immunotherapy targeting mast cells by studying the mechanisms underlying mast cell function in cancer immunosuppression. Between January 2015 and December 2017, the tumor tissues of 40 patients with gastric cancer (GC) were collected and grouped in Lihuili Hospital of Ningbo City, China. Pathological sections were prepared and an immunofluorescence assay was performed to analyze the expression of forkhead Box Protein P3 (FOXP3), tryptase, TGFβ1, TGF-βR, IL-9, IL-9R and Oxford 40 ligand (OX40L). Then, the correlations between FOXP3 and tryptase, TGFβ1 and tryptase expression, and the expression of OX40L in patients with GC with different stages were analyzed. The results revealed that high levels of mast cells were present in patients GC, and tryptase and FOXP3 expressions were positively correlated. Mast cells regulate T regulatory (reg) cells in the gastric tumor microenvironment by secreting TGFβ1. Tregs, in turn, promote the survival of mast cells in the tumor microenvironment by producing IL-9. Furthermore, OX40L expression in mast cells was significantly associated with Tumor-Node-Metastasis staging of GC. Overall, the present study reported a positive feedback system that functions through TGFβ1 and IL-9 to allow cross-talk between Tregs and mast cells. Moreover, OX40L may be a potential target for the diagnosis and treatment of GC. These results may provide a new strategy for tumor immunotherapy targeting mast cells.
Mast cell-based molecular subtypes and signature associated with clinical outcome in early-stage lung adenocarcinoma.
Bao Xuanwen,Shi Run,Zhao Tianyu,Wang Yanfang
Mast cells are a major component of the immune microenvironment in tumour tissues and modulate tumour progression by releasing pro-tumorigenic and antitumorigenic molecules. Regarding the impact of mast cells on the outcomes of patients with lung adenocarcinoma (LUAD) patient, several published studies have shown contradictory results. Here, we aimed at elucidating the role of mast cells in early-stage LUAD. We found that high mast cell abundance was correlated with prolonged survival in early-stage LUAD patients. The mast cell-related gene signature and gene mutation data sets were used to stratify early-stage LUAD patients into two molecular subtypes (subtype 1 and subtype 2). The neural network-based framework constructed with the mast cell-related signature showed high accuracy in predicting response to immunotherapy. Importantly, the prognostic mast cell-related signature predicted the survival probability and the potential relationship between TP53 mutation, c-MYC activation and mast cell activities. The meta-analysis confirmed the prognostic value of the mast cell-related gene signature. In summary, this study might improve our understanding of the role of mast cells in early-stage LUAD and aid in the development of immunotherapy and personalized treatments for early-stage LUAD patients.
Interleukin-17-positive mast cells influence outcomes from BCG for patients with CIS: Data from a comprehensive characterisation of the immune microenvironment of urothelial bladder cancer.
Dowell Alexander C,Cobby Ellen,Wen Kaisheng,Devall Adam J,During Vinnie,Anderson Jane,James Nicholas D,Cheng Kar K,Zeegers Maurice P,Bryan Richard T,Taylor Graham S
The tumour immune microenvironment is considered to influence cancer behaviour and outcome. Using a panel of markers for innate and adaptive immune cells we set out to characterise and understand the bladder tumour microenvironment of 114 patients from a prospective multicentre cohort of newly-diagnosed bladder cancer patients, followed-up for 4.33±1.71 years. We found IL-17-positive cells were significantly increased in primary and concomitant carcinoma in situ (CIS), p<0.0001, a highly malignant lesion which is the most significant single risk factor for disease progression. Further characterisation of the tumour immunophenotype identified IL-17+ cells as predominantly mast cells rather than T-cells, in contrast to most other tumour types. Expression of the IL-17-receptor in bladder tumours, and functional effects and gene expression changes induced by IL-17 in bladder tumour cells in vitro suggest a role in tumour behaviour. Finally, we assessed the effects of IL-17 in the context of patient outcome, following intravesical BCG immunotherapy which is the standard of care; higher numbers of IL-17+ cells were associated with improved event-free survival (p = 0.0449, HR 0.2918, 95% CI 0.08762-0.9721) in patients with primary and concomitant CIS (n = 41), we propose a model of IL-17+ Mast cells mechanism of action. Thus, in the context of bladder CIS, IL-17+ mast cells predict favourable outcome following BCG immunotherapy indicative of a novel mechanism of BCG immunotherapy in UBC and could form the basis of a stratified approach to treatment.
Increased intratumoral mast cells foster immune suppression and gastric cancer progression through TNF-α-PD-L1 pathway.
Lv Yipin,Zhao Yongliang,Wang Xianhua,Chen Na,Mao Fangyuan,Teng Yongsheng,Wang Tingting,Peng Liusheng,Zhang Jinyu,Cheng Ping,Liu Yugang,Kong Hui,Chen Weisan,Hao Chuanjie,Han Bin,Ma Qiang,Zou Quanming,Chen Jun,Zhuang Yuan
Journal for immunotherapy of cancer
BACKGROUND:Mast cells are prominent components of solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, the nature, regulation, function, and clinical relevance of mast cells in human gastric cancer (GC) are presently unknown. METHODS:Flow cytometry analyses were performed to examine level and phenotype of mast cells in samples from 114 patients with GC. Multivariate analysis of prognostic factors for overall survival was performed using the Cox proportional hazards model. Kaplan-Meier plots for patient survival were performed using the log-rank test. Mast cells, T cells and tumor cells were isolated or generated, stimulated and/or cultured for in vitro and in vivo function assays. RESULTS:Patients with GC showed a significantly higher mast cell infiltration in tumors. Mast cell levels increased with tumor progression and independently predicted reduced overall survival. These tumor-infiltrating mast cells accumulated in tumors by CXCL12-CXCR4 chemotaxis. Intratumoral mast cells expressed higher immunosuppressive molecule programmed death-ligand 1 (PD-L1), and mast cells induced by tumors strongly express PD-L1 proteins in both time-dependent and dose-dependent manners. Significant correlations were found between the levels of PD-L1 mast cells and pro-inflammatory cytokine TNF-α in GC tumors, and tumor-derived TNF-α activated NF-κB signaling pathway to induce mast cell expression of PD-L1. The tumor-infiltrating and tumor-conditioned mast cells effectively suppressed normal T-cell immunity through PD-L1 in vitro, and tumor-conditioned mast cells contributed to the suppression of T-cell immunity and the growth of human GC tumors in vivo; the effect could be reversed by blocking PD-L1 on these mast cells. CONCLUSION:Thus, our results illuminate novel immunosuppressive and protumorigenic roles of mast cells in GC, and also present a novel mechanism in which PD-L1 expressing mast cells link the proinflammatory response to immune tolerance in the GC tumor milieu.
Mast cells as targets for immunotherapy of solid tumors.
Oldford Sharon A,Marshall Jean S
Mast cells have historically been studied mainly in the context of allergic disease. In recent years, we have come to understand the critical importance of mast cells in tissue remodeling events and their role as sentinel cells in the induction and development of effective immune responses to infection. Studies of the role of mast cells in tumor immunity are more limited. The pro-tumorigenic role of mast cells has been widely reported. However, mast cell infiltration predicts improved prognosis in some cancers, suggesting that their prognostic value may be dependent on other variables. Such factors may include the nature of local mast cell subsets and the various activation stimuli present within the tumor microenvironment. Experimental models have highlighted the importance of mast cells in orchestrating the anti-tumor events that follow immunotherapies that target innate immunity. Mast cells are long-lived tissue resident cells that are abundant around many solid tumors and are radiation resistant making them unique candidates for combined treatment modalities. This review will examine some of the key roles of mast cells in tumor immunity, with a focus on potential immunotherapeutic interventions that harness the sentinel role of mast cells.
Mast Cells in the Tumor Microenvironment.
Aponte-López Angélica,Muñoz-Cruz Samira
Advances in experimental medicine and biology
Mast cells are tissue-resident, innate immune cells that play a key role in the inflammatory response and tissue homeostasis. Mast cells accumulate in the tumor stroma of different human cancer types, and increased mast cell density has been associated to either good or poor prognosis, depending on the tumor type and stage. Mast cells play a multifaceted role in the tumor microenvironment by modulating various events of tumor biology, such as cell proliferation and survival, angiogenesis, invasiveness, and metastasis. Moreover, tumor-associated mast cells have the potential to shape the tumor microenvironment by establishing crosstalk with other tumor-infiltrating cells. This chapter reviews the current understanding of the role of mast cells in the tumor microenvironment. These cells have received much less attention than other tumor-associated immune cells but are now recognized as critical components of the tumor microenvironment and could hold promise as a potential target to improve cancer immunotherapy.