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    Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study. Delanoy Nicolas,Michot Jean-Marie,Comont Thibault,Kramkimel Nora,Lazarovici Julien,Dupont Romain,Champiat Stéphane,Chahine Claude,Robert Caroline,Herbaux Charles,Besse Benjamin,Guillemin Aude,Mateus Christine,Pautier Patricia,Saïag Philippe,Madonna Emanuela,Maerevoet Marie,Bout Jean-Christophe,Leduc Charlotte,Biscay Pascal,Quere Gilles,Nardin Charlée,Ebbo Mikael,Albigès Laurence,Marret Grégoire,Levrat Virginie,Dujon Cécile,Vargaftig Jacques,Laghouati Salim,Croisille Laure,Voisin Anne-Laure,Godeau Bertrand,Massard Christophe,Ribrag Vincent,Marabelle Aurélien,Michel Marc,Lambotte Olivier The Lancet. Haematology BACKGROUND:Anti-programmed cell death 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) antibodies are novel immunotherapies for cancer that can induce immune-related adverse events (irAEs). These adverse events can involve all organs, including the haemopoietic system. Thus far, haematological irAEs (haem-irAEs) have not been extensively characterised. This study aims to provide a comprehensive report of the haem-irAEs induced by anti-PD-1 or anti-PD-L1. METHODS:In this descriptive observational study, we included consecutive patients aged at least 18 years with grade 2 or worse haem-irAEs induced by anti-PD-1 or anti-PD-L1 immunotherapy registered in three French pharmacovigilance databases: the Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC; a prospective registry of patients treated with anti-PD-1 or anti-PD-L1 at a single centre), the ImmunoTOX committee of Gustave Roussy (a national referral database of suspected irAEs in patients treated with immunotherapy), and the registry of the Centre de Référence des Cytopénies Auto-Immunes de l'Adulte (CeReCAI; a national database of autoimmune cytopenias). Cases were reviewed by a central committee; adverse events had to be classed as certainly or probably related to anti-PD-1 or anti-PD-L1 therapy, and their severity was assessed according to the Common Terminology Criteria for Adverse Events (version 4.03). The primary endpoint was clinical description of haem-irAEs, as reported in all databases, and their frequency, as reported in the prospective REISAMIC registry. FINDINGS:We screened 948 patients registered in the three databases from June 27, 2014, to June 29, 2018 (745 from REISAMIC, 190 from the ImmunoTOX committee, and 13 from CeReCAI). 35 patients (21 men and 14 women) with haem-irAEs related to anti-PD-1 or anti-PD-L1 were included in the study. Of 745 patients in the REISAMIC registry treated with anti-PD-1 or anti-PD-L1, four had haem-irAEs, giving a frequency of 0·5%. Median age in the 35 patients was 65 years (IQR 51-75), and the most common tumour types were melanoma (15 [43%] patients), non-small-cell lung cancer (12 [34%] patients), and lymphoma (four [11%] patients). 20 (57%) patients received nivolumab, 14 (40%) received pembrolizumab, and one (3%) received atezolizumab. Among the 35 patients, neutropenia, autoimmune haemolytic anaemia, and immune thrombocytopenia were the most common types of haem-irAE (each in nine patients [26%]), followed by pancytopenia or aplastic anaemia (five patients [14%]), bicytopenia (one patients with thrombocytopenia plus anaemia and one patient with neutropenia plus anaemia [6%]), and pure red cell aplasia (one patient [3%]). The maximum grade of severity was grade 2 in three (9%) patients, grade 3 in five (14%) patients, and grade 4 in 25 (71%) patients; two (6%) patients died from febrile neutropenia during haem-irAE related to anti-PD-1. Haem-irAEs resolved in 21 (60%) of the 35 patients. INTERPRETATION:Haem-irAEs induced by PD-1 or PD-L1 inhibitors are rare but potentially life-threatening events. The most common clinical presentations are neutropenia, autoimmune haemolytic anaemia, immune thrombocytopenia, and aplastic anaemia. Investigations into earlier detection and better management are warranted. FUNDING:Gustave Roussy and Gustave Roussy Immunotherapy Program. 10.1016/S2352-3026(18)30175-3
    Laminin γ2-mediating T cell exclusion attenuates response to anti-PD-1 therapy. Li Lei,Wei Jia-Ru,Dong Jun,Lin Qing-Guang,Tang Hong,Jia Yong-Xu,Tan Wanlin,Chen Qing-Yun,Zeng Ting-Ting,Xing Shan,Qin Yan-Ru,Zhu Ying-Hui,Li Yan,Guan Xin-Yuan Science advances PD-1/PD-L1 blockade therapies provide notable clinical benefits for patients with advanced cancers, but the factors influencing the effectiveness of the treatment remain incompletely cataloged. Here, the up-regulation of laminin γ2 (Ln-γ2) predicted the attenuated efficacy of anti-PD-1 drugs and was associated with unfavorable outcomes in patients with lung cancer or esophageal cancer. Furthermore, Ln-γ2 was transcriptionally activated by transforming growth factor-β1 (TGF-β1) secreted from cancer-associated fibroblasts via JNK/AP1 signaling, which blocked T cell infiltration into the tumor nests by altering the expression of T cell receptors. Coadministration of the TGF-β receptor inhibitor galunisertib and chemotherapy drugs provoked vigorous antitumor activity of anti-PD-1 therapy in mouse tumor models. Therefore, Ln-γ2 may represent a useful biomarker to optimize clinical decisions and predict the response of cancer patients to treatment with anti-PD-1 drugs. 10.1126/sciadv.abc8346
    The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Kumagai Shogo,Togashi Yosuke,Kamada Takahiro,Sugiyama Eri,Nishinakamura Hitomi,Takeuchi Yoshiko,Vitaly Kochin,Itahashi Kota,Maeda Yuka,Matsui Shigeyuki,Shibahara Takuma,Yamashita Yasuho,Irie Takuma,Tsuge Ayaka,Fukuoka Shota,Kawazoe Akihito,Udagawa Hibiki,Kirita Keisuke,Aokage Keiju,Ishii Genichiro,Kuwata Takeshi,Nakama Kenta,Kawazu Masahito,Ueno Toshihide,Yamazaki Naoya,Goto Koichi,Tsuboi Masahiro,Mano Hiroyuki,Doi Toshihiko,Shitara Kohei,Nishikawa Hiroyoshi Nature immunology Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently required. Here, we show that the frequency of PD-1CD8 T cells relative to that of PD-1 regulatory T (T) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8 T cells and T cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1CD8 T cells and enhanced PD-1 T cell-mediated immunosuppression. A profound reactivation of effector PD-1CD8 T cells rather than PD-1 T cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies. 10.1038/s41590-020-0769-3
    PD-1-Expressing SARS-CoV-2-Specific CD8 T Cells Are Not Exhausted, but Functional in Patients with COVID-19. Rha Min-Seok,Jeong Hye Won,Ko Jae-Hoon,Choi Seong Jin,Seo In-Ho,Lee Jeong Seok,Sa Moa,Kim A Reum,Joo Eun-Jeong,Ahn Jin Young,Kim Jung Ho,Song Kyoung-Ho,Kim Eu Suk,Oh Dong Hyun,Ahn Mi Young,Choi Hee Kyoung,Jeon Ji Hoon,Choi Jae-Phil,Kim Hong Bin,Kim Young Keun,Park Su-Hyung,Choi Won Suk,Choi Jun Yong,Peck Kyong Ran,Shin Eui-Cheol Immunity Memory T cell responses have been demonstrated in COVID-19 convalescents, but ex vivo phenotypes of SARS-CoV-2-specific T cells have been unclear. We detected SARS-CoV-2-specific CD8 T cells by MHC class I multimer staining and examined their phenotypes and functions in acute and convalescent COVID-19. Multimer cells exhibited early differentiated effector-memory phenotypes in the early convalescent phase. The frequency of stem-like memory cells was increased among multimer cells in the late convalescent phase. Cytokine secretion assays combined with MHC class I multimer staining revealed that the proportion of interferon-γ (IFN-γ)-producing cells was significantly lower among SARS-CoV-2-specific CD8 T cells than those specific to influenza A virus. Importantly, the proportion of IFN-γ-producing cells was higher in PD-1 cells than PD-1 cells among multimer cells, indicating that PD-1-expressing, SARS-CoV-2-specific CD8 T cells are not exhausted, but functional. Our current findings provide information for understanding of SARS-CoV-2-specific CD8 T cells elicited by infection or vaccination. 10.1016/j.immuni.2020.12.002
    The Paradoxical Roles of Inflammation during PD-1 Blockade in Cancer. Hill Marcelo,Segovia Mercedes,Russo Sofía,Girotti Maria Romina,Rabinovich Gabriel A Trends in immunology Recent studies have reported paradoxical roles of inflammation in tumor immunity triggered by PD-1 checkpoint antibody (Ab) blockade. Here, we elaborate on this controversy and propose a new perspective that might help understand this paradox. Since inflammatory cytokines and PD-1 blockade are known to target different subsets of exhausted CD8 T cells, we propose that the timing at which anti-PD-1 Ab therapy and cytokine modulation occur might determine the fate of exhausted CD8 T cells and perhaps, the clinical outcome of immunotherapeutic modalities. 10.1016/j.it.2020.09.003
    Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells. Stanczak Michal A,Siddiqui Shoib S,Trefny Marcel P,Thommen Daniela S,Boligan Kayluz Frias,von Gunten Stephan,Tzankov Alexandar,Tietze Lothar,Lardinois Didier,Heinzelmann-Schwarz Viola,von Bergwelt-Baildon Michael,Zhang Wu,Lenz Heinz-Josef,Han Younghun,Amos Christopher I,Syedbasha Mohammedyaseen,Egli Adrian,Stenner Frank,Speiser Daniel E,Varki Ajit,Zippelius Alfred,Läubli Heinz The Journal of clinical investigation First-generation immune checkpoint inhibitors, including anti-CTLA-4 and anti-programmed death 1 (anti-PD-1) antibodies, have led to major clinical progress, yet resistance frequently leads to treatment failure. Thus, new targets acting on T cells are needed. CD33-related sialic acid-binding immunoglobulin-like lectins (Siglecs) are pattern-recognition immune receptors binding to a range of sialoglycan ligands, which appear to function as self-associated molecular patterns (SAMPs) that suppress autoimmune responses. Siglecs are expressed at very low levels on normal T cells, and these receptors were not until recently considered as interesting targets on T cells for cancer immunotherapy. Here, we show an upregulation of Siglecs, including Siglec-9, on tumor-infiltrating T cells from non-small cell lung cancer (NSCLC), colorectal, and ovarian cancer patients. Siglec-9-expressing T cells coexpressed several inhibitory receptors, including PD-1. Targeting of the sialoglycan-SAMP/Siglec pathway in vitro and in vivo resulted in increased anticancer immunity. T cell expression of Siglec-9 in NSCLC patients correlated with reduced survival, and Siglec-9 polymorphisms showed association with the risk of developing lung and colorectal cancer. Our data identify the sialoglycan-SAMP/Siglec pathway as a potential target for improving T cell activation for immunotherapy. 10.1172/JCI120612
    Current Possibilities of Gynecologic Cancer Treatment with the Use of Immune Checkpoint Inhibitors. Grywalska Ewelina,Sobstyl Małgorzata,Putowski Lechosław,Roliński Jacek International journal of molecular sciences Despite the ongoing progress in cancer research, the global cancer burden has increased to 18.1 million new cases and 9.6 million deaths in 2018. Gynecological cancers, such as ovarian, endometrial, and cervical cancers, considerably contribute to global cancer burden, leading to $5,862.6, $2,945.7, and $1,543.9 million of annual costs of cancer care, respectively. Thus, the development of effective therapies against gynecological cancers is still a largely unmet medical need. One of the novel therapeutic approaches is to induce anti-cancer immunity by the inhibition of the immune checkpoint pathways using monoclonal antibodies. The molecular targets for monoclonal antibodies are cytotoxic T lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed death-ligand 1 (PD-L1). The rationale for the use of immune checkpoint inhibitors in patients with gynecological cancers was based on the immunohistological studies showing high expression levels of PD-1 and PD-L1 in those cancers. Currently available immune checkpoint inhibitors include nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and ipilimumab. The efficacy and safety of these inhibitors, used as monotherapy and with combination with chemotherapy, is being currently evaluated in several clinical studies. As the results are promising, more clinical trials are being planned, which may lead to the development of efficient therapies for gynecological cancer patients. 10.3390/ijms20194705
    Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma. Kim Chang Gon,Kim Chan,Yoon Sang Eun,Kim Kyung Hwan,Choi Seong Jin,Kang Beodeul,Kim Hye Ryun,Park Su-Hyung,Shin Eui-Cheol,Kim Yeun-Yoon,Kim Dae Jung,Chung Hyun Cheol,Chon Hong Jae,Choi Hye Jin,Lim Ho Yeong Journal of hepatology BACKGROUND & AIMS:Programmed cell death-1 (PD-1) inhibitor treatment can cause hyperprogressive disease (HPD), but the incidence, outcome, and predictive factors of HPD are unknown in patients with hepatocellular carcinoma (HCC). Herein, we assessed the existence and factors predictive of HPD in patients with advanced HCC treated with nivolumab. METHODS:We enrolled 189 patients with advanced HCC treated with nivolumab. Occurrence of HPD was investigated using tumour growth dynamics based on tumour growth kinetics (TGK) and tumour growth rate (TGR) before and after treatment, or time to treatment failure. We additionally analysed patients treated with regorafenib (n = 95) or best supportive care (BSC)/placebo (n = 103) after progression on sorafenib to compare tumour growth dynamics. RESULTS:Flare-up of tumour growth was observed in a fraction of patients upon PD-1 blockade, indicating the occurrence of HPD. Based on distinct patterns of disease progression exclusively observed in the nivolumab-treated cohort, but not in the regorafenib- or BSC/placebo-treated cohorts, 4-fold increases in TGK and TGR ratios as well as a 40% increase in TGR were the cut-off values used to define HPD; 12.7% of the patients (24/189) treated with nivolumab met all these criteria. Patients with HPD had worse progression-free survival (hazard ratio [HR] 2.194; 95% CI 1.214-3.964) and overall survival (HR 2.238; 95% CI 1.233-4.062) compared to patients with progressive disease without HPD. More than 90% of patients with HPD missed the opportunity for subsequent treatment because of rapid clinical deterioration. An elevated neutrophil-to-lymphocyte ratio (>4.125) was associated with HPD and an inferior survival rate. CONCLUSIONS:HPD occurs in a fraction of patients with HCC who receive PD-1 inhibitor treatment. Analyses of the baseline immune profile and on-treatment tumour growth dynamics could enable optimal patient selection and earlier identification of HPD. LAY SUMMARY:Hyperprogressive disease is an unexpected response pattern observed in patients treated with an immune checkpoint inhibitor. This study revealed that hyperprogressive disease occurs in a fraction of patients with advanced hepatocellular carcinoma treated with an anti-PD-1 antibody, providing evidence to encourage careful monitoring of patients to prevent clinical deterioration induced by PD-1 blockade. 10.1016/j.jhep.2020.08.010
    Neoadjuvant PD-1 inhibitor (Sintilimab) in NSCLC. Gao Shugeng,Li Ning,Gao Shunyu,Xue Qi,Ying Jianming,Wang Shuhang,Tao Xiuli,Zhao Jun,Mao Yousheng,Wang Bing,Shao Kang,Lei Wendong,Wang Dali,Lv Fang,Zhao Liang,Zhang Fan,Zhao Ziran,Su Kai,Tan Fengwei,Gao Yibo,Sun Nan,Wu Dawei,Yu Yue,Ling Yun,Wang Zhijie,Duan Chunjian,Tang Wei,Zhang Lei,He Shun,Wu Ning,Wang Jie,He Jie Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer INTRODUCTION:Programmed death receptor-1 (PD-1) inhibitors have shown efficacy in first-line treatment of NSCLC; however, evidence of PD-1 inhibitor as neoadjuvant treatment is limited. This is a phase 1b study to evaluate the safety and outcome of PD-1 inhibitor in neoadjuvant setting. METHODS:Treatment-naive patients with resectable NSCLC (stage IA-IIIB) received two cycles of sintilimab (200 mg, intravenously, day 1 out of 22). Operation was performed between day 29 and 43. Positron emission tomography-computed tomography scans were obtained at baseline and before the operation. The primary end point was safety. Efficacy end points included rate of major pathologic response (MPR) and objective response rate. Expression of programmed cell death ligand 1 was also evaluated (registration number: ChiCTR-OIC-17013726). RESULTS:A total of 40 patients enrolled, all of whom received two doses of sintilimab and 37 underwent radical resection. A total of 21 patients (52.5%) experienced neoadjuvant treatment-related adverse events (TRAEs). Four patients (10.0%) experienced grade 3 or higher neoadjuvant TRAEs, and one patient had grade 5 TRAE. Eight patients achieved radiological partial response, resulting in an objective response rate of 20.0%. Among 37 patients, 15 (40.5%) achieved MPR, including six (16.2%) with a pathologic complete response in primary tumor and three (8.1%) in lymph nodes as well. Squamous cell NSCLC exhibited superior response compared with adenocarcinoma (MPR: 48.4% versus 0%). Decrease of maximum standardized uptake values after sintilimab treatment correlated with pathologic remission (p < 0.00001). Baseline programmed cell death ligand 1 expression of stromal cells instead of tumor cells was correlated with pathologic regression (p = 0.0471). CONCLUSIONS:Neoadjuvant sintilimab was tolerable for patients with NSCLC, and 40.5% MPR rate is encouraging. The decrease of maximum standardized uptake values after sintilimab might predict pathologic response. 10.1016/j.jtho.2020.01.017
    CDK5 Inhibition Abrogates TNBC Stem-Cell Property and Enhances Anti-PD-1 Therapy. Bei Yuncheng,Cheng Nan,Chen Ting,Shu Yuxin,Yang Ye,Yang Nanfei,Zhou Xinyu,Liu Baorui,Wei Jia,Liu Qin,Zheng Wei,Zhang Wenlong,Su Huifang,Zhu Wei-Guo,Ji Jianguo,Shen Pingping Advanced science (Weinheim, Baden-Wurttemberg, Germany) Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, in which the higher frequency of cancer stem cells (CSCs) correlates with the poor clinical outcome. An aberrant activation of CDK5 is found to associate with TNBC progression closely. CDK5 mediates PPAR phosphorylation at its Ser 273, which induces CD44 isoform switching from CD44s to CD44v, resulting in an increase of stemness of TNBC cells. Blocking CDK5/pho-PPAR significantly reduces CD44v+ BCSCs population in tumor tissues, thus abrogating metastatic progression in TNBC mouse model. Strikingly, diminishing stemness transformation reverses immunosuppressive microenvironment and enhances anti-PD-1 therapeutic efficacy on TNBC. Mechanistically, CDK5 switches the E3 ubiquitin ligase activity of PPAR and directly protects ESRP1 from a ubiquitin-dependent proteolysis. This finding firstly indicates that CDK5 blockade can be a potent strategy to diminish stemness transformation and increase the response to PD-1 blockade in TNBC therapy. 10.1002/advs.202001417
    Simultaneous Inhibition of LSD1 and TGF-B Enables Eradication of Poorly Immunogenic Tumors with anti-PD-1 Treatment. Sheng Wanqiang,Liu Yi,Chakraborty Damayanti,Debo Brian,Shi Yang Cancer discovery Epigenetic regulators are a class of promising targets in the combination with immune checkpoint inhibitors for cancer treatment, but the impact of the broad effects of perturbing epigenetic regulators on tumor immunotherapy remains to be fully explored. Here we show that ablation of the histone demethylase LSD1 in multiple tumor cells induces TGF-B expression, which exerts an inhibitory effect on T cell immunity through suppressing the cytotoxicity of intratumoral CD8+ T cells and consequently dampens the antitumor effect of LSD1 ablation-induced T cell infiltration. Importantly, concurrent depletion of LSD1 and TGF-B in combination with PD-1 blockade significantly increases both CD8+ T cell infiltration and cytotoxicity, leading to eradication of poorly immunogenic tumors and a long-term protection from tumor re-challenge. Thus, combining LSD1 inhibition with blockade of TGF-B and PD-1 may represent a promising triple combination therapy for treating certain refractory tumors. 10.1158/2159-8290.CD-20-0017
    Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-risk Resected Melanoma. Patrinely J Randall,Johnson Rebecca,Lawless Aleigha R,Bhave Prachi,Sawyers Amelia,Dimitrova Maya,Yeoh Hui Ling,Palmeri Marisa,Ye Fei,Fan Run,Davis Elizabeth J,Rapisuwon Suthee,Long Georgina V,Haydon Andrew,Osman Iman,Mehnert Janice M,Carlino Matteo S,Sullivan Ryan J,Menzies Alexander M,Johnson Douglas B JAMA oncology Importance:Agents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined. Objective:To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy. Design, Setting, and Participants:This retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included. Main Outcomes and Measures:Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation). Results:Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, developed in 167 (43.2%) patients, of which most (n = 161; 96.4%) were mild (grade 1 or 2) and most persisted until last available follow-up (n = 143; 85.6%). Endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (11 of 15; 73.3%), and ocular events (5 of 8; 62.5%) were particularly likely to become chronic. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs. Conclusion and Relevance:In this multicenter cohort study, chronic irAEs associated with anti-PD-1 therapy appear to be more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low grade. The risks of chronic irAEs should be integrated into treatment decision-making. 10.1001/jamaoncol.2021.0051
    The PD-1/PD-L1-Checkpoint Restrains T cell Immunity in Tumor-Draining Lymph Nodes. Dammeijer Floris,van Gulijk Mandy,Mulder Evalyn E,Lukkes Melanie,Klaase Larissa,van den Bosch Thierry,van Nimwegen Menno,Lau Sai Ping,Latupeirissa Kitty,Schetters Sjoerd,van Kooyk Yvette,Boon Louis,Moyaart Antien,Mueller Yvonne M,Katsikis Peter D,Eggermont Alexander M,Vroman Heleen,Stadhouders Ralph,Hendriks Rudi W,Thüsen Jan von der,Grünhagen Dirk J,Verhoef Cornelis,van Hall Thorbald,Aerts Joachim G Cancer cell PD-1/PD-L1-checkpoint blockade therapy is generally thought to relieve tumor cell-mediated suppression in the tumor microenvironment but PD-L1 is also expressed on non-tumor macrophages and conventional dendritic cells (cDCs). Here we show in mouse tumor models that tumor-draining lymph nodes (TDLNs) are enriched for tumor-specific PD-1 T cells which closely associate with PD-L1 cDCs. TDLN-targeted PD-L1-blockade induces enhanced anti-tumor T cell immunity by seeding the tumor site with progenitor-exhausted T cells, resulting in improved tumor control. Moreover, we show that abundant PD-1/PD-L1-interactions in TDLNs of nonmetastatic melanoma patients, but not those in corresponding tumors, associate with early distant disease recurrence. These findings point at a critical role for PD-L1 expression in TDLNs in governing systemic anti-tumor immunity, identifying high-risk patient groups amendable to adjuvant PD-1/PD-L1-blockade therapy. 10.1016/j.ccell.2020.09.001
    Tumor-derived exosomes in the PD-1/PD-L1 axis: Significant regulators as well as promising clinical targets. Liang Benhui,Hu Ximin,Ding Yinghe,Liu Mujun Journal of cellular physiology Programmed cell death-1 (PD-1) is a negative coreceptor mainly expressed on the surface of activated T cells. The binding of PD-1 to its ligand PD-L1 significantly induces non-reactivity of T cells to maintain the balance of autoimmunity and immune tolerance. It is reported that tumor cells highly express PD-L1 to restrict cellular immune response, which is one of the most important mechanisms for tumor to mediate immune escape. Cancer immunotherapy targeting PD-1/PD-L1 has achieved remarkable success so far. Tumor-derived exosomes (TEXs) are lipid bilayer vesicles released by tumor cells in an endosome-dependent manner, mediating communication between tumor cells and adjacent cells in the tumor microenvironment. Through signals transmitted by TEXs, tumor can alter the biological characteristics of these cells to promote tumor growth and metastasis. Recent studies have demonstrated that TEXs not only carry tumor-derived PD-L1, but are also closely related to PD-1/PD-L1 expression on target cells. The primary focus of this review will be on how TEXs regulate the PD-1/PD-L1 axis to promote tumor progression, and the promising clinical applications targeting TEXs and exosomal PD-L1. 10.1002/jcp.30197
    Emerging Role of Ubiquitination in the Regulation of PD-1/PD-L1 in Cancer Immunotherapy. Hu Xiaoli,Wang Jing,Chu Man,Liu Yi,Wang Zhi-Wei,Zhu Xueqiong Molecular therapy : the journal of the American Society of Gene Therapy A growing amount of evidence suggests that ubiquitination and deubiquitination of programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) play crucial roles in the regulation of PD-1 and PD-L1 protein stabilization and dynamics. PD-1/PD-L1 is a major coinhibitory checkpoint pathway that modulates immune escape in cancer patients, and its engagement and inhibition has significantly reshaped the landscape of tumor clearance. The abnormal ubiquitination and deubiquitination of PD-1/PD-L1 influence PD-1/PD-L1-mediated immunosuppression. In this review, we describe the ubiquitination- and deubiquitination-mediated modulation of PD-1/PD-L1 signaling through a variety of E3 ligases and deubiquitinating enzymes (DUBs). Moreover, we briefly expound on the anticancer potential of some agents that target related E3 ligases, which further modulate the ubiquitination of PD-1/PD-L1 in cancers. Therefore, this review reveals the development of a highly promising therapeutic approach for cancer immunotherapy by targeting PD-1/PD-L1 ubiquitination. 10.1016/j.ymthe.2020.12.032