The IL17RA/IL17 pathway sustain the induction of effector and memory cytotoxic T cell responses against tumors

C RODRIGUEZ; J TOSELLO BOARI; C ARAUJO FURLAN; F CANALE; CG BECCARIA; S BOSSIO; S BOCCARDO; A GRUPPI; C MONTES; EV ACOSTA RODRIGUEZ

Cancún, Quintana Roo

Congreso; XII Congress of the Latin American Association of Immunology and XXIII Congress of the Mexican Society of Immunology; 2019

17 cytokines play important roles in protecting the host against extracellular pathogens and promoting inflammatory pathology in autoimmune diseases (1). In cancer, several reports have shown that IL-17 can have both anti- and pro-tumoral effects (2). However, the particular mechanism that determines its tumor promoting or suppressive functions in a given tumor are not known yet. Previously, our team and others demonstrated that IL-17 family plays a central role in the induction of CD8+ T cell (CTL) and NK responses (3). As these subsets are critical for tumor resistance, we evaluated the role of IL-17 signaling in the induction of the anti-tumoral CTL immunity and tumor progression. To this end, B6 (WT), IL-17RA KO (RKO) and IL-17A/F double KO (DKO) mice were injected with tumor cell lines exhibiting progressor (B16-SIY and MCA101-OVA) and regressor (MC57-SIY) growth patterns (4, 5). We determined that volumes of B16 and MC57, but not MCA101, tumors were increased in RKO and DKO mice compared to WT mice at several days post injection (dpi). To further understand these differences in tumor progression, we evaluated the primary CTL response against B16 and MC57 tumors. We determined that 20 days upon B16 injection, RKO and DKO mice showed reduced numbers of total and tumor-specific CD8+ T cells (p<0.05) and increased expression of several inhibitory receptors (PD1, LAG3, TIM3) (p<0.05) within tumor infiltrating lymphocytes in comparison to WT counterparts. Similarly, analysis of the primary CTL response against MC57 demonstrated that compared to WT controls, DKO mice presented reduced numbers of tumor-specific CTL in draining-lymph nodes at d12pi (p<0.05). Also, tumor-specific CTL displayed decreased numbers of cells with memory phenotype (CD62L+CD127+) (p<0.05). As the memory CTL response developed in MC57-SIY-immunized WT mice is critical for host protection against challenge with B16-SIY tumors, we evaluated whether RKO and DKO mice were able to generate protective SIY-specific CTL memory. To this end, we challenged MC57-SIY immunized mice with B16-SIY tumor cells and determined tumor growth until day 32 post challenge (pc). While most of immunized WT mice (75%) rejected the B16 tumors, immunized DKO and RKO mice were less protected as only few mice (around 20%) were tumor free at d32pc (p<0.05). Accordingly, blood and tumors of DKO mice showed reduced frequency of SIY-specific CTL (p<0.05) as well as decreased tumor-specific cells with a memory effector phenotype (CD44+CD62L-; p<0.001) in comparison to WT controls at day 8pc. Altogether, our results indicate that the IL-17/IL-17RA pathway modulates primary and secondary antitumor CTL responses and may influence tumor progression in certain cancers. Further studies on the role IL-17 signaling within the tumor microenvironment will provide rationale to understand the risks and benefits of targeting IL-17 in a given tumor.