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

项目摘要 成功的过继性细胞疗法（ACT）的主要障碍是获得性抗性的发展， 当癌细胞下调或丢失时，癌细胞对肿瘤特异性T细胞变得不可见 抗原（指抗原低/丧失抗性肿瘤细胞，或ALR）。在本建议书中，我们将探讨 通过p38 MAPK抑制肿瘤微环境（TME）重编程促进强大的树突状细胞的作用 细胞（DC）驱动的抗ALR免疫，以防止ACT中的获得性耐药性。在我们的体内初步研究中， 用CAR T细胞和Ralimetinib（一种有效的和选择性的p38 MAPK抑制剂， 癌症患者）在TME内赋予免疫原性DC标记特征。值得注意的是，T 细胞+雷利美替尼治疗根除了已建立的肿瘤，并通过以下方式实现了长期无肿瘤生存： 触发了强大的宿主抗ALR免疫，而单独的CAR T细胞ACT重现了临床情况， 癌症复发的可能性。基于这些新的发现，我们假设p38 MAPK是一种新的蛋白激酶， 控制DC分化的关键分子开关，其中p38抑制促进免疫原性DC 转录程序并诱导有效的抗ALR免疫以防止T细胞中的获得性抗性 疗法目的1将确定NF κ B B/Stat 5信号转导通过抑制PPAR γ在分子水平上的作用。 雷利美替尼介导的DC富集的机制。目的2将确定NF-κ B B（p50）依赖性 体内p38介导物处理后DC中ALR清除的病毒模拟。这项研究可能会揭示一个新的 预防ACT中肿瘤复发的机制。从我们提出的目标中获得的数据可能会产生急需的 有证据表明，将临床测试的Ralimetinib从靶向肿瘤细胞中的p38 MAPK重新用于 免疫细胞的免疫应答可以诱导ACT的完全和持久的应答。这一相关工作可以 为以后的临床试验打下基础。

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.