Abstract 5181: The role of Neuropilin-1 signaling in CD4 conventional T cell immune function in non-small cell lung cancer

Abstract Despite advances in therapy, lung cancer remains the leading cause of cancer related deaths. In non-small cell lung cancer (NSCLC), a subset of tumor-infiltrating CD4 T cells express Neuropilin-1 (NRP1), a transmembrane protein that binds to multiple ligands with diverse functions in tumor and immune cells. Recent studies reveal that NRP1 can be induced upon T cell receptor stimulation and that NRP1 signaling promotes increased stabilization and function of CD4+ FoxP3+ regulatory T cells (Tregs), while signaling on CD8 T cells results in inhibition of CD8 T cell migration and cytotoxicity; therefore, NRP1 is implicated as a newly defined immune checkpoint protein. The functional role of NRP1 in CD4+ FoxP3- T conventional cells (CD4 Tconv) and the ligands involved are largely unexplored. We have found that human lung cancer malignant pleural effusions (MPE) from a subset of metastatic lung cancer patients contain both NRP1+ and NRP1- CD4 Tconv cells, providing a relevant clinical setting to study the function of NRP1 in human T cells. Our preliminary studies reveal that MPE-derived NRP1+ CD4 Tconv cells have altered expression of CD25, suggestive of a more activated state as compared to that of NRP1- CD4 Tconv cells. Additionally, we have observed disproportionate cell death of NRP1+ CD4 Tconv cells that can be partially rescued with anti-NRP1 monoclonal antibodies (mAbs). Surviving NRP1+ cells are more likely to express PD-1 and secrete effector cytokines. In our murine NSCLC model carrying key driver mutations KrasG12D P53−/− Lkb1−/− and higher tumor mutational burden (KPL-3M), analysis of tumor-infiltrating CD4 Tconv cells confirm that NRP1+ CD4 T cells are preferentially found within tumors and with higher PD-1 expression as compared to NRP1- cells. Furthermore, treatment with anti-NRP1 mAbs confers anti-tumor efficacy in this model, indicating that NRP1 is a functionally important inhibitor of host anti-tumor immune responses. These data suggest that CD4 Tconv cells expressing NRP1 are activated but prone to cell death, warranting further investigation into its potential as a therapeutic target for NSCLC. Citation Format: Bitta P. Kahangi, Raymond J. Lim, Jensen Abascal, William P. Crosson, Edgar Perez Reyes, Camelia Dumitras, Linh M. Tran, Kostyantyn Krysan, Ramin Salehi-Rad, Steven M. Dubinett, Bin Liu. The role of Neuropilin-1 signaling in CD4 conventional T cell immune function in non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5181.