Rescuing Anti-tumor Responses of TCR-Td T Cells by NKG2D-stimulation

经遗传修饰以表达与肿瘤抗原反应的T细胞受体的T细胞的连续细胞转移 TCR-Td T细胞）已经成为治疗恶性肿瘤的最有前途的方法之一。 然而，最近的临床研究报告客观临床反应率低于30%。提供了合理的 为了解释这些反应，研究表明，在携带肿瘤的宿主中，转移的T细胞遇到 以免疫抑制为特征的不适宜居住的环境。因此，使TCR-Td CD 8 + T细胞 对这些负面环境线索的抵抗可以显着改善癌症患者的临床反应。 鉴于NKG 2D受体的刺激作用，我们研究了其控制CD 8 + T细胞的能力。 镇压我们的数据首次显示，NKG 2D刺激人TCR-Td CD 8 + T细胞（类似于 而小鼠CD 8 + T细胞对TGF-β抑制产生完全抵抗。 和增强的针对黑素瘤的治疗性抗肿瘤应答。我们的数据还表明，NKG 2D激活 TCR-Td CD 8 + T细胞对TGF-β抑制的抵抗伴随着两个负调节因子的上调。 TGF-β信号调节因子RGS 3和PDPK 1。虽然这些发现描述了NKG 2D在人类中的新功能， CD 8 + T细胞，这些通路如何在NKG 2D信号传导和抑制抗性中相互联系 还有待确定。我们假设NKG 2D诱导的TCR-Td CD 8 + T细胞对 抑制由PI 3 K、Grb 2和JNK途径以及RGS 3和PDPK 1的组合作用介导。 因此，本提案的目的是剖析NKG 2D利用的近端和远端信号通路 赋予对TGF-β的抗性并增强抗肿瘤免疫力。为了做到这一点，我们将使用人类和老鼠 转导以表达针对酪氨酸酶肽/HLA-A2和h3 T转基因小鼠的TCR的CD 8 + T细胞， 它们表达相同的受体。我们的研究提出了一个新的范例;人类CD 8 + T细胞可以被 通过NKG 2D信号传导进行转录操纵以实现对TGF-β的抗性。我们认为， 在ACT之前，通过NKG 2D激动剂可以容易地调节TCR-Td CD 8 + T细胞，以提高其存活率 和治疗性抗肿瘤能力。

Adoptive cell transfer of T cells genetically modified to express a T cell receptor reactive to a tumor antigen (TCR-Td T cells) has emerged as one of the most promising approaches for the treatment of malignancies. However, recent clinical studies report objective clinical response rates lower than 30%. Providing a plausible explanation for these responses, studies have shown that, in tumor-bearing hosts, transferred T cells encounter an inhospitable environment characterized by immune suppression. Hence, rendering TCR-Td CD8+ T cells resistant to these negative environmental cues could significantly improve clinical responses in cancer patients. Given the stimulatory role of the NKG2D receptor, we investigated its ability to control CD8+ T cell suppression. Our data show for the first time that NKG2D stimulation in human TCR-Td CD8+ T cells (similar to those used in clinical trials) and mouse CD8+ T cells results in complete resistance to suppression by TGF-¿ and augmented therapeutic anti-tumor responses against melanoma. Our data also show that NKG2D-activated TCR-Td CD8+ T cell resistance to suppression by TGF-¿ is accompanied by the upregulation of two negative regulators of TGF-¿ signaling, RGS3 and PDPK1. While these findings depict novel functions for NKG2D in CD8+ T cells, how these pathways are interconnected in NKG2D signaling and resistance to suppression remains to be determined. We hypothesize that NKG2D-induced resistance of TCR-Td CD8+ T cells to suppression is mediated by the PI3K, Grb2, and JNK pathways and the combined effects of RGS3 and PDPK1. Thus, the objective of this proposal is to dissect the proximal and distal signaling pathways utilized by NKG2D to confer resistance to TGF-¿ and enhanced anti-tumor immunity. To do this, we will use human and mouse CD8+ T cells transduced to express a TCR against a tyrosinase peptide/HLA-A2 and h3T transgenic mice, which express the same receptor. Our study posits a new paradigm; human CD8+ T cells can be transcriptionally manipulated by NKG2D signaling to achieve resistance to TGF-¿. We believe that human TCR-Td CD8+ T cells could be easily conditioned prior to ACT by an NKG2D agonist to enhance their survival and therapeutic anti-tumor capacity.