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

项目摘要 成功采用细胞疗法(ACT)的一个主要障碍是获得性耐药的发展，这是 当癌细胞下调或丢失时，肿瘤特异性T细胞看不到癌细胞，就会发生这种情况 抗原(S)(指抗原低/抗丢失的肿瘤细胞，简称ALR)。在这项建议中，我们将探讨 抑制p38 MAPK对肿瘤微环境(TME)重编程促进树突状细胞生长的作用 细胞(DC)驱动抗ALR免疫以防止ACT的获得性耐药。在我们体内的初步研究中， 与CAR T细胞和雷美替尼(一种有效的选择性p38 MAPK抑制剂)联合治疗 癌症患者)在TME内赋予免疫原性DC签名特征。令人惊讶的是，T车 细胞+雷米米尼疗法根除已建立的肿瘤，并通过以下方式实现长期无瘤生存 触发强大的宿主抗ALR免疫，而仅CAR T细胞ACT概括了临床情景 由ALRS介导的癌症复发。基于这些新的发现，我们假设p38MAPK是一种 控制DC分化的关键分子开关，其中p38抑制促进免疫原性DC 转录程序并诱导强大的抗ALR免疫以防止T细胞的获得性耐药 心理治疗。目标1将通过抑制在分子中的作用来确定核转录因子PPAR B/STAT5信号的作用 雷米美替尼对DC的致富机制。目标2将确定依赖于核因子B(P50)的作用 P38抑制剂体内处理后树突状细胞的病毒模拟清除ALR。这项研究可能会揭示一部小说 ACT预防肿瘤复发的机制。来自我们提议的AIMS的数据可能会产生急需的数据 有证据表明，改变临床测试的雷美替尼靶向肿瘤细胞中的p38 MAPK的目的是为了 免疫细胞的变化可能会在ACT中诱导完全和持久的反应。这部与翻译相关的作品可能 然后为未来的临床试验奠定基础。

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.