RNA-binding Protein PCBP1/hnRNP E1 is an Intracellular Checkpoint for Balancing Effector versus Regulatory T Cells

Distinct lineages of T cells can act in response to various environmental cues to either drive or restrict immune-mediated pathology. Immunotherapy involving the block of cell surface immune checkpoints CTLA-4 and PD-1/PD-L1 has revolutionized cancer treatment across a wide spectrum of malignancies. However, additional immune regulatory mechanisms remain to be discovered, and will facilitate development of next generation agents to overcome resistance to current therapies. We now report that the RNA-binding protein, PCBP1, is critical for stabilizing effector T cell functions by limiting expression of T effector cell-intrinsic Treg-commitment programs and subverting expression of immune-suppressive signals. Indeed, T cell-specific deletion of Pcbp1 increased Treg development, enlisted multiple inhibitory checkpoint molecules including PD-1, TIGIT and VISTA on TILs, and thwarted anti-tumor immunity. Our results demonstrate a critical role for PCBP1 as an intracellular checkpoint for balancing effector versus Treg cells and also suggest PCBP1 as a novel target for cancer immunotherapy. Spleen mRNA profiles of 6-8 weeks old wild type (WT) and Pcbp1f/fCD4-Cre male mice were generated by deep sequencing, in quadruplicate, using Illumina HiSeq3000.

不同谱系的T细胞可响应多种环境信号，进而介导或抑制免疫相关病理的发生。靶向阻断细胞表面免疫检查点CTLA-4与PD-1/PD-L1的免疫治疗方案，已在多种恶性肿瘤的临床治疗中实现革命性突破。然而，目前仍有诸多潜在的免疫调控机制有待发掘，这些机制将助力下一代免疫治疗药物的研发，以克服当前疗法的耐药性难题。本研究发现，RNA结合蛋白（RNA-binding protein）PCBP1可通过限制效应T细胞固有的调节性T细胞（regulatory T cell，简称Treg）分化程序，并抑制免疫抑制信号的表达，从而稳定效应T细胞的功能，发挥关键调控作用。实验证实，T细胞特异性敲除Pcbp1会促进Treg细胞的分化，诱导肿瘤浸润淋巴细胞（tumor-infiltrating lymphocytes，简称TIL）表面表达PD-1、TIGIT、VISTA等多种抑制性免疫检查点分子，并削弱机体的抗肿瘤免疫应答。本研究结果表明，PCBP1作为胞内免疫检查点，在平衡效应T细胞与Treg细胞的比例中发挥关键调控作用，同时提示PCBP1可作为癌症免疫治疗的新型潜在靶点。本研究采用Illumina HiSeq3000测序平台，以四重生物学重复的方式，对6-8周龄野生型（WT）及Pcbp1f/fCD4-Cre雄性小鼠的脾脏组织mRNA进行深度测序，获取其脾脏转录组表达谱。