Lycera Corp. Ann Arbor, Michigan.
University of Michigan Medical School, Ann Arbor, Michigan.
Cancer Immunol Res. 2019 Jul;7(7):1054-1063. doi: 10.1158/2326-6066.CIR-18-0714. Epub 2019 May 7.
Activation of RORγ with synthetic small-molecule agonists has been shown to enhance type 17 effector (CD4 Th17 and CD8 Tc17 cells) cell functions and decrease immunosuppressive mechanisms, leading to improved antitumor efficacy in adoptive cell transfer and syngeneic murine tumor models. However, whether Tc17 cells possess intrinsic cytotoxicity and the mechanism they use to lyse target cells is controversial. We report here that Tc17 cells were lytic effectors dependent on perforin and granzyme A. In contrast to Tc1 cells, Tc17 cells resisted activation-induced cell death and maintained granzyme A levels, which conferred the ability to lyse target cells in serial encounters. Thus, although the acute lytic capacity of Tc17 cells could be inferior to Tc1 cells, comparable lysis was achieved over time. In addition to direct lytic activity, Tc17 cells infiltrated early into the tumor mass, recruited other CD8 T cells to the tumor, and enhanced the survival and lytic capability of these cells during repeated target encounters. Synthetic RORγ agonists further augmented Tc17 survival and lytic activity and , controlling tumor growth not only through direct cytotoxicity, but also through recruitment and improved function of other effector cells in the tumor microenvironment, which suggests complementary and cooperate activities for effective immunotherapy.
用合成的小分子激动剂激活 RORγ 已被证明可以增强 1 型 17 效应（CD4 Th17 和 CD8 Tc17 细胞）细胞的功能，并减少免疫抑制机制，从而提高过继细胞转移和同基因小鼠肿瘤模型中的抗肿瘤疗效。然而，Tc17 细胞是否具有内在的细胞毒性以及它们用来裂解靶细胞的机制仍存在争议。我们在此报告 Tc17 细胞是依赖于穿孔素和颗粒酶 A 的溶细胞效应物。与 Tc1 细胞相反，Tc17 细胞抵抗激活诱导的细胞死亡并维持颗粒酶 A 水平，这赋予了在连续遭遇中裂解靶细胞的能力。因此，尽管 Tc17 细胞的急性裂解能力可能不如 Tc1 细胞，但随着时间的推移，可实现相当的裂解。除了直接的裂解活性外，Tc17 细胞还早期浸润到肿瘤块中，招募其他 CD8 T 细胞到肿瘤中，并在反复靶标遭遇时增强这些细胞的存活和裂解能力。合成的 RORγ 激动剂进一步增强了 Tc17 的存活和裂解活性，并控制肿瘤生长不仅通过直接细胞毒性，而且通过募集和改善肿瘤微环境中其他效应细胞的功能，这表明有效的免疫治疗需要互补和协作的活动。
