Abstract 33: Revitalizing CAR-T cells for TNBC: Targeting phosphorylation of TCF7 to overcome T cell exhaustion

Abstract Breast cancer stands as the second leading cause of cancer-related deaths among women in the United States, with triple-negative breast cancer (TNBC) representing the most aggressive subtype. Although immune checkpoint inhibitors (ICI) demonstrated durable response in some TNBC patients, the added benefit of current FDA-approved ICI in combination with chemotherapy is estimated to be only around 10%. Fortunately, TNBC displays the highest number of tumor-infiltrating lymphocytes (TILs), compared to other BC subtypes, indicating an optimal context for the survival of T cells. Therefore, CAR-T therapy emerges as a promising therapeutic option for TNBC patients. Expanding the application of CAR-T therapies to solid tumors, including breast cancer, remains challenging. One of the key hurdles lies in the immunosuppressive tumor microenvironment, where the T cell receptor experiences long-term exposure to tumor antigens, leading to T cell exhaustion. This state impedes the T cells' capacity to efficiently target and eliminate cancer cells. Identifying key regulatory mechanisms downstream of the T cell receptor holds the potential to revolutionize existing immunotherapeutic strategies. In our study, we discovered that the presence of the master transcriptional factor of T cell stemness, TCF1, in CD8+ T cells, is essential for controlling TNBC tumors. TCF1 undergoes phosphorylation by LCK, a crucial component of initiating T cell receptor signaling, upon T cell activation. We found this phosphorylation site is indispensable for TCF1's transcriptional activities, inhibiting the downstream program of T-cell persistence and causing T-cell exhaustion. Reversing this process, either through LCK inhibition or introducing a non-phosphorylated form of TCF1, results in a more sustained CAR-T cell-mediated anti-tumor response. Our findings reveal the significance of TCF1 post-translational modification in the development and longevity of stem-like CD8+ T cells, bridging the gap between TCR signaling and transcriptional and epigenetic programs of stem-like CD8+ T cells. This insight contributes to a potential cure for TNBC by maintaining T cell persistence. Citation Format: Zhou Jiang, Yu-Yi Chu, Heng-Huan Lee, Mien-Chie Hung, Liuqing Yang, Chunru Lin. Revitalizing CAR-T cells for TNBC: Targeting phosphorylation of TCF7 to overcome T cell exhaustion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 33.