Abstract
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 in vitro and in vivo, 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.
Highlights
Retinoic acid receptor–related orphan receptor g (RORg) is a master transcription factor that controls the differentiation and maintenance of the CD4þ and CD8þ type 17 effector T-cell subsets, Th17 and Tc17, respectively [1]
The prognosis can be poor in some situations where IL17 induces angiogenesis, inflammation, and promotes the initiation and early growth of some tumors [9, 10], the presence of RORgþ type 17 T cells or their hallmark cytokines such as IL17A and GM-CSF is associated with improved antitumor effects in many cancers [11,12,13,14,15,16,17]
We have previously reported that only a fraction of human T cells coexpress both RORg and IL17A, suggesting that RORg and IL17A may play distinct roles in Tc17-mediated antitumor immunity [18]
Summary
Retinoic acid receptor–related orphan receptor g (RORg) is a master transcription factor that controls the differentiation and maintenance of the CD4þ and CD8þ type 17 effector T-cell subsets, Th17 and Tc17, respectively [1]. Type 17 T cells participate in regulation of bacterial, viral, and fungal infections; autoimmune disease; and antitumor immunity [2]. Type 17 T cells can mediate potent and durable tumor growth inhibition when transferred to tumor-bearing animals [6,7,8]. The prognosis can be poor in some situations where IL17 induces angiogenesis, inflammation, and promotes the initiation and early growth of some tumors [9, 10], the presence of RORgþ type 17 T cells or their hallmark cytokines such as IL17A and GM-CSF is associated with improved antitumor effects in many cancers [11,12,13,14,15,16,17]. We have previously reported that only a fraction of human T cells coexpress both RORg and IL17A, suggesting that RORg and IL17A may play distinct roles in Tc17-mediated antitumor immunity [18]
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