作者: Luke, Jason J ; Poklepovic, Andrew S ; Reeder, Carly ; Christner, Susan M ; Bao, Riyue ; Doerfler, Rose ; Behr, Sarah ; Smith, Katelyn ; Bruno, Tullia C ; Urban, Julie ; Ferris, Robert L ; Dadey, Rebekah E ; Lee, Patrice ; Jelinek, Mark ; Sellitto, Lorenzo ; Soloff, Adam C ; Villaruz, Liza C ; Isett, Brian ; Zandberg, Dan P ; Kulkarni, Aditi ; Newman, Sarah ; Deitrick, Christopher ; Singh, Krishna B ; Davar, Diwakar ; Vujanović, Lazar ; Augustin, Ryan C ; Li, Aofei ; Beumer, Jan H ; Joy, Marion ; Skinner, Heath D ; Najjar, Yana
Patients with tumors that do not respond to immune-checkpoint inhibition often harbor a non-T cell-inflamed tumor microenvironment, characterized by the absence of IFN-γ-associated CD8+ T cell and dendritic cell activation. Understanding the molecular mechanisms underlying immune exclusion in non-responding patients may enable the development of novel combination therapies. p38 MAPK is a known regulator of dendritic and myeloid cells however a tumor-intrinsic immunomodulatory role has not been previously described. Here we identify tumor cell p38 signaling as a therapeutic target to potentiate anti-tumor immunity and overcome resistance to immune-checkpoint inhibitors (ICI). Molecular analysis of tumor tissues from patients with human papillomavirus-negative head and neck squamous carcinoma reveals a p38-centered network enriched in non-T cell-inflamed tumors. Pan-cancer single-cell RNA analysis suggests that p38 activation may be an immune-exclusion mechanism across multiple tumor types. P38 knockdown in cancer cell lines increases T cell migration, and p38 inhibition plus ICI in preclinical models shows greater efficacy compared to monotherapies. In a clinical trial of patients refractory to PD1/L1 therapy, pexmetinib, a p38 inhibitor, plus nivolumab demonstrated deep and durable clinical responses. Targeting of p38 with anti-PD1 has the potential to induce the T cell-inflamed phenotype and overcome immunotherapy resistance.