Eradication of Escaped Variant Tumor Cells for Cancer Immunotherapy

项目摘要 最近，我们发现过继转移CD39KO肿瘤特异性(混合的CD4+和CD8+)T细胞， 导致携带已建立的大肿瘤的小鼠长期存活。出乎意料的是，我们发现这些T 细胞在体内促进抗原丢失变异体(ALV)的杀伤，防止肿瘤复发。此外， 转移CD39KO而不是对照KO，肿瘤特异性T细胞根除包含 10%的ALV，并导致长期无瘤生存和对ALV肿瘤再次攻击的保护 细胞。基于这些新的发现，我们假设肿瘤特异性CD39KO T细胞的转移将 根除大的已建立的肿瘤和防止ALV肿瘤的复发，因为它们能够直接杀死 并诱导抗ALV反应。目标1将确定I型干扰素的产生在 预防ALV肿瘤复发的肿瘤部位。AIM 2将确定CD39KO T细胞在T细胞中的作用 炎性髓系细胞的募集和诱导I型干扰素的产生以清除肿瘤。目标3 将决定人类肿瘤特异性CD39KO T细胞是否也具有这些能力 有效根除人源化小鼠体内的人类肿瘤。这些创新性和机械性的研究将摆脱 阐明CD39KO T细胞介导的抗肿瘤免疫的机制，从而建立一种 将这一发现转化为使用肿瘤特异性T细胞进行更有效的免疫疗法的基础 人类癌症中的亚群。

Project Summary Recently, we discovered that adoptive transfer of CD39KO tumor-specific (mixed CD4+ and CD8+) T cells, resulted in long-term survival of mice bearing large established tumors. Unexpectedly, we found that these T cells promoted killing of antigen-loss-variants (ALVs) in vivo and prevented tumor recurrence. Moreover, transfer of CD39KO, but not control KO, tumor-specific T cells eradicated large chimeric tumors that contained 10% of ALVs and resulted in long-term tumor-free survival and protection against rechallenge with ALV tumor cells. Based on these novel findings, we hypothesize that transfer of tumor-specific CD39KO T cells will eradicate large established tumors and prevent recurrence of ALV tumors, due to their ability to directly kill the tumor cells and induce anti-ALV responses. Aim 1 will determine the contribution of type I IFN production at the tumor site in preventing recurrence of ALV tumors. Aim 2 will determine the role of CD39KO T cells in the recruitment of inflammatory myeloid cells and the induction of type I IFN production for tumor clearance. Aim 3 will determine whether human tumor-specific CD39KO T cells are also endowed with these abilities to effectively eradicate human tumors in humanized mice. These innovative and mechanistic studies will shed light on the mechanisms underlying CD39KO T 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.