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Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers - PubMed

Th17 cells contribute to combination MEK inhibitor and anti-PD-L1 therapy resistance in KRAS/p53 mutant lung cancers - PubMed

Source :

https://pubmed.ncbi.nlm.nih.gov/33972557/

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 ...

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    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.”