A novel T-cell subset able to kill relapsed cancers

项目摘要 癌症治疗中的主要问题是，尽管患者对癌症的最初治疗有反应 缓解后，绝大多数接受治疗的患者会出现肿瘤复发的原发和转移 网站。对于接受免疫治疗的患者，复发的肿瘤细胞经常成为抗原丢失的变种。 (ALV)由于压力和免疫系统的选择。ALV生长是一种重要的机制，通过 哪些肿瘤在免疫攻击中存活下来并进行针对单一或多个抗原的免疫治疗 效果不佳。最近，我们发现，当在Th9极化条件下启动时，天真的CD8T细胞 也可以分化为产生IL-9的Tc9亚群(Lu等人，Proc Natl Acad Sci USA，2014)。虽然 与Tc1细胞相比，过继转移肿瘤特异性Tc9细胞在体外对细胞的杀伤作用更弱 对已建立的大黑色素瘤(B16和B16-OVA)和结肠的抗肿瘤反应显著增强 (MC38-gp100)肿瘤。更重要的是，我们的初步研究表明，过继转移的肿瘤 (OVA)特异的Tc9而不是Tc1细胞不仅可以根除表达OVA的肿瘤细胞，还可以根除大的已建立的肿瘤细胞 同时含有OVA表达和OVA阴性的肿瘤细胞以及OVA阴性的嵌合体肿瘤 肿瘤细胞生长在小鼠的对侧侧翼，表明Tc9细胞可以介导杀伤 活体内本地旁观者和远程ALV。基于这些新发现，我们假设Tc9子集 可能是消除原发和复发ALV的癌症免疫治疗的极佳效应器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和 诱导宿主对肿瘤细胞表达的其他抗原的CTL反应，AIM 2将 确定人肿瘤特异性Tc9细胞在体内杀伤人原发肿瘤和ALV肿瘤的潜力。 这些创新性和机械性的研究将有助于阐明Tc9细胞介导的机制。 并因此将为将这一发现转化为更有效的 在人类癌症中使用肿瘤特异性T细胞亚群的免疫治疗。

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.