PDF(Pubmed)
Abstract：
Immune checkpoint (IC) blockade and adoptive transfer of tumor-specific T-cells (ACT) are two major strategies to treat metastatic melanoma. Their combination can potentiate T-cell activation in the suppressive tumor microenvironment, but the autoimmune adverse effects associated with systemic injection of IC blockers persist with this strategy. ACT of tumor-reactive T-cells defective for IC expression would overcome this issue. For this purpose, PD-1 and TIGIT appear to be relevant candidates, because their co-expression on highly tumor-reactive lymphocytes limits their therapeutic efficacy within the tumor microenvironme,nt. Our study compares the consequences of PDCD1 or TIGIT genetic deletion on anti-tumor properties and T-cell fitness of melanoma-specific T lymphocytes. Transcriptomic analyses revealed down-regulation of cell cycle-related genes in PD-1KO T-cells, consistent with biological observations, whereas proliferative pathways were preserved in TIGITKO T-cells. Functional analyses showed that PD-1KO and TIGITKO T-cells displayed superior antitumor reactivity than their wild-type counterpart in vitro and in a preclinical melanoma model using immunodeficient mice. Interestingly, it appears that TIGITKO T-cells were more effective at inhibiting tumor cell proliferation in vivo, and persist longer within tumors than PD-1KO T-cells, consistent with the absence of impact of TIGIT deletion on T-cell fitness. Taken together, these results suggest that TIGIT deletion, over PD-1 deletion, in melanoma-specific T-cells is a compelling option for future immunotherapeutic strategies.
摘要：
免疫检查点（IC）阻断和肿瘤特异性T细胞（ACT）的过继转移是治疗转移性黑色素瘤的两种主要策略。它们的组合可以增强抑制性肿瘤微环境中的T细胞激活，但与全身注射IC阻滞剂相关的自身免疫不良反应在此策略中持续存在.IC表达缺陷的肿瘤反应性T细胞的ACT将克服这个问题。为此,PD-1和TIGIT似乎是相关的候选人，因为它们在高度肿瘤反应性淋巴细胞上的共表达限制了它们在肿瘤微环境中的治疗功效，NT.我们的研究比较了PDCD1或TIGIT基因缺失对黑色素瘤特异性T淋巴细胞的抗肿瘤特性和T细胞适应性的影响。转录组学分析显示PD-1KOT细胞中细胞周期相关基因的下调，与生物学观察一致，而增殖途径保留在TIGITKOT细胞中。功能分析表明，PD-1KO和TIGITKOT细胞在体外和使用免疫缺陷小鼠的临床前黑色素瘤模型中表现出比其野生型对应物更好的抗肿瘤反应性。有趣的是,看来TIGITKOT细胞在体内更有效地抑制肿瘤细胞增殖，在肿瘤内的存留时间比PD-1KOT细胞长，与TIGIT缺失对T细胞适应性没有影响一致。一起来看,这些结果表明TIGIT缺失，超过PD-1删除，黑色素瘤特异性T细胞是未来免疫治疗策略的一个令人信服的选择.
