Anti-PD-1 antibody-mediated activation of type 17 T-cells undermines checkpoint blockade therapy

Tumors that develop in the genetic LSL-K-ras murine lung cancer model are resistant to anti-PD-1 antibody treatment. Analysis of tumor-bearing lungs from anti-PD-1-treated mice revealed an up to 2.5-fold increase in IL-17-producing T-cells, with minimal change in CD8 T-cell activity. Neutralization of IL-17 concurrent with anti-PD-1 treatment on the other hand, resulted in robust CD8 T-cell activation and a threefold reduction in tumor burden. Loss-of-function studies demonstrated that anti-PD-1 driven activation of CD4 and γδTCR T-cells contributed to IL-17-mediated de-sensitization of CD8 cytotoxic T-cells (CTL) to therapy; and that CTL activation was critical to tumor eradication. Importantly, post-therapy lung Th17 cell prevalence and activity prognosticated treatment efficacy. Consistent with the murine data, analysis of tumor biopsy samples from non-small cell lung cancer (NSCLC) patients revealed that pre-therapy intratumoral CD8/RORc cell ratio correlated with response to immune checkpoint blockade (ICB). These findings provide the initial evidence for a new mechanism of ICB resistance in lung cancer.