Abstract Immunotherapy has significantly improved outcomes for some cancer patients, but many patients, including those with breast cancer, have minimal response to these therapies. Our long-term goal is to enhance the efficacy of immunotherapy in patients with metastatic breast cancer, specifically by targeting short-form Ron (SF-Ron). SF-Ron is one of two transcripts encoded by the Mst1r (Ron) gene and lacks the ligand-binding domain present in the full-length Ron isoform. We previously reported that deletion of host SF-Ron protects against breast cancer lung metastasis in mice by promoting a heightened immune response mediated by T cells. Given the increasing evidence that tissue-specific tumor microenvironments can impact the effectiveness of immunotherapies, we aim to determine whether the loss of host SF-Ron also enhances an immune response in the bone. This is important because bone is the most common site of breast cancer metastasis, and it has been shown that the presence of bone metastases weakens the response to immunotherapies not only in bone but also in other metastatic sites. Using an experimental model of breast cancer bone metastasis, we observed that tumors initially grow in both wild-type (WT) mice and mice lacking SF-Ron (Ron SF-/-), but are subsequently eliminated by the immune system in Ron SF-/-mice. This immune-mediated clearance was associated with increased infiltration of T cells, B cells, and dendritic cells into bone metastases in Ron SF-/- mice compared to WT controls. We also determined that T cells, B cells, and dendritic cells express SF-Ron. Unlike T cells and dendritic cells, the role of B cells in anti-tumor immunity is poorly understood, yet clinical evidence suggests that high infiltration of B cells is associated with improved prognosis in breast cancer. To investigate the importance of B cells in tumor elimination in mice lacking SF-Ron, we performed genetic depletion of B cells in Ron SF-/- mice. Loss of B cells strikingly rescued tumor growth in SF-Ron knockouts and had no effect on tumor growth in WT mice, confirming the necessity of B cells for the anti-tumor immune response in this model, and revealing a novel link between B cells and SF-Ron-mediated protection from tumor growth. RNA sequencing revealed that B cells from Ron SF-/- mice are more proliferative and active in the presence of tumors compared to wild-type B cells, suggesting a role for SF-Ron in regulating B cell activity against tumors. To our knowledge, this is the first study to show expression of SF-Ron in B cells and reveal a role for SF-Ron in B cell function, as well as the first to implicate B cell anti-tumor activity in breast cancer bone metastasis. Future work will assess the contributions of SF-Ron in B cells for tumor clearance using in vitro functional assays and single-cell RNA sequencing. Our data suggest that targeting host SF-Ron could improve outcomes for metastatic breast cancer patients by increasing anti-tumor immune responses, at least in part through stimulating infiltration and activity of B cells in bone metastases. Citation Format: Clint H. Valencia, Jaime Fornetti, Alana L. Welm. Short-form Ron regulates the B cell response in preclinical models of metastatic breast cancer 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 A002.
Valencia et al. (Wed,) studied this question.