Li Xi, Wang Rouzheng, Fan Peiwen, Yao Xuan, Qin Ling, Peng Yanchun, Ma Miaomiao, Asley Neil, Chang Xuimei, Feng Yaning, Hu Yunhui, Zhang Yonghong, Li Chris, Fanning Gregory, Jones Stephanie, Verrill Clare, Maldonado-Perez David, Sopp Paul, Waugh Craig, Taylor Stephen, Mcgowan Simon, Cerundolo Vincenzo, Conlon Christopher, McMichael Andrew, Lu Shichun, Wang Xiyan, Li Ning, Dong Tao
Key Laboratory of Tumor Immunology and Radiation Therapy, Third Affiliated Hospital, Xinjiang Tumor Hospital, Chinese Academy of Medical Sciences (CAMS), Xinjiang Medical University, Ürümqi, China.
Nuffield Department of Medicine (NDM), Chinese Academy of Medical Sciences Oxford Institute (CAMS Oxford Institute), University of Oxford, Oxford, United Kingdom.
Front Oncol. 2019 Oct 25;9:1066. doi: 10.3389/fonc.2019.01066. eCollection 2019.
Cancer patients often display dysfunctional antitumor T-cell responses. Because noteworthy benefits of immune checkpoint pathway blockade, such as programmed cell death protein 1 (PD-1) inhibitors, have been achieved in multiple advanced cancers, the next critical question is which mono-blockade or combinatorial blockade regimens may reinvigorate antitumor T-cell immunity in those cancer patients while limiting immune-related adverse effects. This study recruited, in total, 172 primary cancer patients (131 were blood-tumor-matched patients) who were treatment-naïve prior to the surgeries or biopsies covering the eight most prevalent types of cancer. With access to fresh surgical samples, this study simultaneously investigated the expression level of eight known immune checkpoint receptors [PD-1, cytotoxic T-lymphocyte antigen-4 [CTLA-4], T-cell immunoglobulin and mucin-domain containing-3 [Tim-3], 2B4, killer cell lectin like receptor G1 [KLRG-1], TIGIT, B- and T-lymphocyte attenuator [BTLA], and CD160] on tumor-infiltrating T cells (TILs) and paired circulating T cells in blood from a 131-patient cohort. We found increased an expression of PD-1 and Tim-3 but a decreased expression of BTLA on TILs when compared with peripheral blood from multiple types of cancer. Moreover, our co-expression analysis of key immune checkpoint receptors delineates "shared" subsets as PD-1+Tim-3+TIGIT+2B4+KLRG-1-CTLA-4- and PD-1+TIGIT+2B4+Tim-3-KLRG-1-CTLA-4- from bulk CD8 TILs. Furthermore, we found that a higher frequency of advanced differentiation stage T cells (CD27-CCR7-CD45RA-) among the "shared" subset (PD-1+Tim-3+TIGIT+2B4+KLRG-1-CTLA-4-) in bulk CD8 TILs was associated with poorly differentiated cancer type in cervical cancer patients. To our knowledge, our study is the first comprehensive analysis of key immune checkpoint receptors on T cells in treatment-naïve, primary cancer patients from the eight most prevalent types of cancer. These findings might provide useful information for future design of mono-blockade/combinatorial blockades and/or genetically modified T-cell immunotherapy.
癌症患者常常表现出功能失调的抗肿瘤T细胞反应。由于免疫检查点通路阻断剂，如程序性细胞死亡蛋白1（PD-1）抑制剂，已在多种晚期癌症中取得了显著疗效，下一个关键问题是哪种单药阻断或联合阻断方案能够在限制免疫相关不良反应的同时，重振这些癌症患者的抗肿瘤T细胞免疫。本研究共招募了172例原发性癌症患者（其中131例为血液肿瘤匹配患者），这些患者在接受涵盖八种最常见癌症类型的手术或活检之前均未接受过治疗。通过获取新鲜的手术样本，本研究同时调查了131例患者队列中肿瘤浸润T细胞（TILs）和配对的循环T细胞上八种已知免疫检查点受体[PD-1、细胞毒性T淋巴细胞抗原4（CTLA-4）、含T细胞免疫球蛋白和粘蛋白结构域3（Tim-3）、2B4、杀伤细胞凝集素样受体G1（KLRG-1）、TIGIT、B和T淋巴细胞衰减器（BTLA）以及CD160]的表达水平。我们发现，与多种癌症类型的外周血相比，TILs上PD-1和Tim-3的表达增加，而BTLA的表达降低。此外，我们对关键免疫检查点受体的共表达分析从大量CD8 TILs中界定出“共享”亚群为PD-1+Tim-3+TIGIT+2B4+KLRG-1-CTLA-4-和PD-1+TIGIT+2B4+Tim-3-KLRG-1-CTLA-4-。此外，我们发现，在大量CD8 TILs的“共享”亚群（PD-1+Tim-3+TIGIT+2B4+KLRG-1-CTLA-4-）中，晚期分化阶段T细胞（CD27-CCR7-CD45RA-）的频率较高与宫颈癌患者中低分化癌症类型相关。据我们所知，我们的研究是对来自八种最常见癌症类型的未经治疗的原发性癌症患者T细胞上关键免疫检查点受体的首次全面分析。这些发现可能为未来单药阻断/联合阻断和/或基因改造T细胞免疫疗法的设计提供有用信息。
