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 T 细胞的激活，但与全身注射 IC 阻滞剂相关的自身免疫不良反应仍然存在于这种策略中。 IC 表达缺陷的肿瘤反应性 T 细胞的 ACT 将解决这个问题。为此，PD-1 和 TIGIT 似乎是相关的候选者，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效果。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。转录组分析显示，PD-1KO T 细胞中细胞周期相关基因下调，与生物学观察结果一致，而 TIGITKO T 细胞中则保留了增殖途径。功能分析表明，PD-1KO 和 TIGITKO T 细胞在体外以及使用免疫缺陷小鼠的临床前黑色素瘤模型中表现出比野生型对应物更优异的抗肿瘤反应性。有趣的是，TIGITKO T 细胞似乎比 PD-1KO T 细胞更有效地抑制体内肿瘤细胞增殖，并且在肿瘤内持续时间更长，这与 TIGIT 缺失对 T 细胞健康没有影响是一致的。总而言之，这些结果表明，黑色素瘤特异性 T 细胞中的 TIGIT 删除（相对于 PD-1 删除）是未来免疫治疗策略的一个令人信服的选择。© 2024 作者。经泰勒许可出版

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.© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.