ProS1-MerTK signaling in CD4 T cells: implications for TIL expansion and functionality.

Cancer immunotherapy predominantly targets CD8 T cells, but recent evidence highlights the importance of CD4 T cells in adoptive cell therapy (ACT). The TAM receptor MerTK regulates immune responses and has been shown to provide costimulatory signals in CD8 T cells. However, its role in CD4 T cells remains poorly understood. Here, we demonstrate that ProS1-MerTK signaling is upregulated in activated CD4 T cells, where it enhances central memory formation, metabolic fitness, and proliferation. Mechanistically, ProS1-MerTK signaling was linked to type 1 immune responses, suggesting a regulatory role in CD4 T cell polarization. Using CRISPR-Cas9-mediated knockout, we found that loss of MerTK reduced CD4 T cell fitness, function, and polarization. Furthermore, when ProS1 was added during the expansion of tumor-infiltrating lymphocytes (TILs) from advanced melanoma biopsies, it showed potential to promote favorable CD4 T cell memory and helper phenotypes, increase stemness, and reduce exhaustion - features associated with improved responses to ACT. These findings establish ProS1-MerTK as a key pathway for modulating CD4 T cell functionality and highlight its therapeutic potential to enhance TIL-based ACT outcomes.