P38 MAPK is a molecular switch that controls the acquired resistance in adoptive cell therapy

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Project Summary A major obstacle to successful adoptive cell therapy (ACT) is the development of acquired resistance, which can occur due to cancer cells become invisible to tumor-specific T cells when cancer cells downregulate or lost the antigen(s) (refers to antigen-low/loss resistant tumor cells, or ALRs). In this proposal, we will explore the role of reprogramming of tumor microenvironment (TME) by p38 MAPK inhibition to promote a robust dendritic cell (DC)-driving anti-ALR immunity to prevent acquired resistance in ACT. In our in vivo preliminary studies, co-treatment with CAR T cells and Ralimetinib (a potent and selective inhibitor of p38 MAPK developed for cancer patients) confers immunogenic DC signature characteristics within TME. Strikingly, CAR T cell+Ralimetinib-treatment eradicated established tumors and resulted in long-term tumor-free survival by triggering a robust host anti-ALR immunity, whereas CAR T cell ACT alone recapitulated the clinical scenario of cancer relapse mediated by ALRs. Based on these novel findings, we hypothesize that p38 MAPK is a critical molecular switch that controls DC differentiation, where p38 inhibition promotes an immunogenic DC transcriptional program and induces potent anti-ALR immunity to prevent the acquired resistance in T cell therapy. Aim 1 will determine the role of NFB/Stat5 signaling by repression of PPAR in the molecular mechanisms of Ralimetinib-mediated DC enrichment. Aim 2 will determine the role of NFB (p50)-dependent viral mimicry in DCs for ALR clearance after p38 inhibitor-treatment in vivo. This study may uncover a novel mechanism for preventing tumor relapse in ACT. Data from our proposed Aims may yield critically needed evidence that repurposing the clinically tested Ralimetinib from targeting p38 MAPK in tumor cells toward that of immune cells may induce a complete and durable response in ACT. This translationally relevant work could then lay the foundation for future clinical trials.