Abstract Breast cancer is a significant health challenge, killing more than 500,000 people each year worldwide. Most of these deaths are caused by metastasis. Immunotherapy has emerged as a promising avenue in cancer treatment, yet its efficacy in breast cancer, particularly in treating metastatic disease, remains limited. Recent studies from our lab established that a specific isoform of Ron tyrosine kinase, short-form Ron (sfRon), is a key mediator of anti-tumor immune responses in mouse models of metastatic breast cancer. We reported that sfRon is expressed by T cells, and deletion of short-form Ron (sfRon-/-) elicits a robust anti-tumor T cell response. sfRon-/- mice are protected from MMTV-PyMT breast cancer lung metastasis due to a profound T cell infiltration into tumor micro-metastases. However, little is known about the mechanism of how sfRon could modulate the anti-tumor immune response. My project aims to define how sfRon regulates the anti-tumor T cell response at both molecular and cellular levels. In vitro we demonstrate that sfRon-/- T cells are more proliferative in response to T cell receptor stimulation compared to wildtype T cells. In vivo, sfRon-/- splenic T cells express higher levels of TCF1, a transcription factor important in T cell development and differentiation. Finally, to complement our tumor studies, we used a viral infection model to study antigen specific T cell responses and the development of memory T cells. At both peak of response and memory timepoints, sfRon-/- mice have more viral antigen specific T cells capable of making key cytokines such as interferon gamma compared to wildtype mice. Together these data suggest that loss of sfRon reprograms T cell signaling leading to more robust T cell responses in both tumor and viral infection settings. Ongoing work will elucidate the molecular mechanism of how sfRon regulates T cell activation, effector function and differentiation through RNA sequencing, in vitro assays and adoptive transfer studies. We anticipate that this work will not only advance the understanding sfRon in immunity but will also shed light on the therapeutic use of Ron inhibitors as both anti-cancer treatments and immunomodulators. Citation Format: Marija Nadjsombati, Alicia Shu-Chin. Lai, Alana Welm. Short-Form Ron Tyrosine Kinase Deficiency Uncovers a Critical Regulator of Anti-Tumor T Cell Responses abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C031.
Nadjsombati et al. (Wed,) studied this question.