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 patients treated with PD-1 blockade predicted poorer overall survival and response in melanoma and predicated poorer response to anti-PD1 in NSCLC patients. Here we show a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade.
Highlights
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
We identified a reciprocal expression between PD-L1 and MAPK signaling when lung tumors were treated with MEK inhibitor or anti-PD-L1, respectively, validating a promising dual combinatorial therapy approach previously reported in multiple cancer types[13,33,34,35,36]
We further demonstrate that IL-17 and IL-22 cytokines secreted by Th17 cells are directly responsible for promoting drug resistance, invasion, and metastasis
Summary
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. Previous clinical trials combining MEK inhibitor with anti-PD-L1 in solid tumors (melanoma, NSCLC, and colorectal cancers) show a manageable safety profile, but with only moderate tumor response[13,14,15] Taken together, these trials have demonstrated disappointing results, even in the KRAS and BRAF mutant subgroups, and despite a demonstrated increase in CD8+ T-cell infiltration into tumors with the treatment, suggesting that other secondary factors may limit the efficacy of the dual treatment. Our findings reveal the molecular rationale for combining MEK inhibitors with PD-L1 blockade, identify the mechanism of combinatorial drug resistance, identify potential predictive markers of immunotherapy response, and validate a promising triple combinatorial treatment strategy for patients with KRAS mutant lung cancer
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