Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance inKRAS/p53mutant lung cancers

Abstract

Understanding resistance mechanisms to targeted therapies and immune checkpoint blockade in mutant KRAS lung cancers is critical to developing novel combination therapies and improving patient survival. Here, we show that MEK inhibition enhanced PD-L1 expression while PD-L1 blockade upregulated MAPK signaling in mutant KRAS lung tumors. Combined MEK inhibition with anti-PD-L1 synergistically reduced lung tumor growth and metastasis, but tumors eventually developed resistance to sustained combinatorial therapy. Multi-platform profiling revealed that resistant lung tumors have increased infiltration of Th17 cells, which secrete IL-17 and IL-22 cytokines to promote lung cancer cell invasiveness and MEK inhibitor resistance. Antibody depletion of IL-17A in combination with MEK inhibition and PD-L1 blockade markedly reduced therapy-resistance in vivo. Clinically, increased expression of Th17-associated genes in melanoma patients treated with PD-1 blockade predicted poorer overall survival and response.Our study validates a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade.All statistical analysis were performed using GraphPad Prism software version 8.0.0. Unless otherwise noted, a one-way ANOVA post-hoc Tukey test was used for multi-group comparisons while unpaired Student t-test (two-tailed) was performed for two-group comparisons. A p-value of less than 0.05 was considered statistically significant.