A novel T-cell subset able to kill relapsed cancers

项目概要 癌症治疗的主要问题是，尽管患者对癌症的初始治疗有反应 缓解后，绝大多数接受治疗的患者会出现原发性和转移性肿瘤复发 网站。对于接受免疫治疗的患者，复发的肿瘤细胞经常变成抗原丢失变异体 （ALV）由于免疫系统的压力和选择而产生。 ALV 的生长是一个重要的机制 哪些肿瘤能够在免疫攻击中幸存下来并提供针对单个或多个抗原的免疫疗法 无效。最近，我们发现，当在 Th9 极化条件下启动时，幼稚 CD8 T 细胞 还可以分化为产生 IL-9 的 Tc9 子集（Lu 等人，Proc Natl Acad Sci USA，2014）。虽然 与 Tc1 细胞相比，体外细胞溶解性较小，肿瘤特异性 Tc9 细胞的过继转移会引发 对大型黑色素瘤（B16 和 B16-OVA）和结肠的抗肿瘤反应显着增强 (MC38-gp100) 肿瘤。更重要的是，我们的初步研究表明，过继性转移的肿瘤 (OVA) 特异性 Tc9 而不是 Tc1 细胞不仅根除表达 OVA 的肿瘤细胞，还根除大量已建立的肿瘤细胞 含有 OVA 表达和 OVA 阴性肿瘤细胞以及 OVA 阴性的嵌合肿瘤 肿瘤细胞生长在小鼠的对侧侧腹，表明 Tc9 细胞可以介导杀伤 本地旁观者和远程 ALV 体内。基于这些新发现，我们假设 Tc9 子集 可能是用于根除原发性和复发性 ALV 的癌症免疫疗法的极好的效应 T 细胞亚群 肿瘤。目标 1 将确定 Tc9 细胞是否以及如何通过表位扩散介导杀伤 ALV 诱导针对肿瘤细胞表达的其他抗原的宿主 CTL 反应，目标 2 将 确定人类肿瘤特异性 Tc9 细胞在体内杀死人类原发性肿瘤和 ALV 肿瘤的潜力。 这些创新和机制研究将揭示 Tc9 细胞介导的潜在机制 抗肿瘤免疫，从而为将这一发现转化为更有效的药物奠定了基础 在人类癌症中使用肿瘤特异性 T 细胞亚群进行免疫疗法。

Project Summary The major problem in cancer treatment is that, although patients respond to the initial treatment with cancer remission, the vast majority of the treated patients will have tumor recurrence in the primary and metastatic sites. For patients receiving immunotherapy, the recurring tumor cells frequently become antigen-loss-variants (ALVs) due to pressure and selection by the immune system. ALV outgrowth is an important mechanism by which tumors survive the immune attack and render immunotherapies targeting a single or multiple antigens ineffective. Recently, we discovered that when primed under Th9-polarizing conditions, naïve CD8+ T cells could also differentiate into an IL-9-producing Tc9 subset (Lu et al, Proc Natl Acad Sci USA, 2014). Although less cytolytic in vitro as compared with Tc1 cells, adoptive transfer of tumor-specific Tc9 cells elicits a significantly greater antitumor response against large established melanoma (B16 and B16-OVA) and colon (MC38-gp100) tumors. More importantly, our preliminary studies showed that adoptively transferred tumor (OVA)-specific Tc9 but not Tc1 cells eradicated not only OVA-expressing tumor cells but also large established chimeric tumors containing both OVA-expressing and OVA-negative tumor cells, as well as OVA-negative tumor cells grown on the contralateral flank of mice, indicating that the Tc9 cells could mediate the killing of local bystander and remote ALVs in vivo. Based on these novel findings, we hypothesize that the Tc9 subset may be a superb effector T-cell subset for cancer immunotherapy to eradicate primary and recurrent ALV tumors. Aim 1 will determine whether and how Tc9 cells mediate killing of ALVs via epitope spreading and induction of a host CTL response against other antigens expressed by the tumor cells, and Aim 2 will determine the potential of human tumor-specific Tc9 cells in killing human primary and ALV tumors in vivo. These innovative and mechanistic studies will shed light on the mechanisms underlying Tc9 cell-mediated antitumor immunity and will thus establish a foundation for translating this discovery into more effective immunotherapies using tumor-specific T-cell subsets in human cancers.