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， 导致携带大的已建立肿瘤的小鼠的长期存活。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体（ALV）的杀伤并防止肿瘤复发。此外，委员会认为， 转移CD39KO，而不是对照KO，肿瘤特异性T细胞根除了含有 10%的ALV，并导致长期无肿瘤生存和对ALV肿瘤再激发的保护 细胞基于这些新的发现，我们假设肿瘤特异性CD39 KO T细胞的转移将导致肿瘤细胞的凋亡。 由于ALV具有直接杀死肿瘤细胞的能力， 肿瘤细胞并诱导抗ALV应答。目标1将确定I型IFN产生的贡献， 在预防ALV肿瘤复发的肿瘤部位。目的2将确定CD39 KO T细胞在免疫应答中的作用。 募集炎性骨髓细胞和诱导I型IFN产生以清除肿瘤。目标3 将确定人肿瘤特异性CD39 KO T细胞是否也具有这些能力， 在人源化小鼠中有效地根除人类肿瘤。这些创新和机械的研究将摆脱 阐明了CD39 KO T细胞介导的抗肿瘤免疫的机制，从而建立了 将这一发现转化为使用肿瘤特异性T细胞的更有效的免疫疗法的基础 人类癌症的亚型。

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.