Key Points
• In the current preclinical trial, researchers demonstrated that in mutant KRAS lung tumors, MEK inhibition promoted PD-L1 expression, whereas PD-L1 blockade upregulated MAPK signaling. Combined MEK inhibition with anti-PD-L1 decreased lung tumor growth and metastases in a synergistic fashion. Tumors, however, eventually developed resistance to prolonged combinatorial therapy. Importantly, resistant lung tumors demonstrated increased infiltration of Th17 cells.
• “Our identification that the Th17-associated cytokine IL-17 promotes resistance to anti-PD-L1 alone or in combination with MEK inhibition validates a novel triple combinatorial therapeutic strategy for lung cancer patients, consistent with observations that IL-17 is involved in tumor progression,” the authors wrote. “Moreover, the increase in cancer cell IL-6 expression from combination therapy as well as the role of Th17 in autoimmunity suggests that IL-17 blockade could potentially ameliorate the observed clinical adverse events owing to immune checkpoint blockade.
• The triple combinatorial treatment strategy is advantageous because all 3 agents have already received FDA approval. Of note, IL-17 drugs are FDA approved to treat psoriasis.
• The authors wrote, “Results from our study emphasize the need for accessible lung cancer patient data sets with matched pre- and post-treatment biopsies to predict patient response and identify potential combination therapeutic strategies to improve patient survival.”