Abstract
The bone is the most common site of metastasis and the usual first site of recurrence in metastatic breast cancer. Bone metastasis is incurable and causes severe pain with significant bone loss in breast cancer patients. Current treatments for bone metastasis aim to diminish bone loss; however, most patients still progress on current therapies, making it critical to identify new therapeutic targets. We have identified the receptor Recepteur d'Origine Nantais (RON) as a target for treating metastatic breast cancer. RON is the receptor for the macrophage stimulating protein (MSP) and has both tumor-intrinsic and -extrinsic roles in metastasis. The gene encoding RON (MST1R in human or Stk in mouse) gives rise to two transcripts coding for full-length RON (FL-RON) and short-form RON (SF-RON) isoforms, where SF-RON lacks the ligand-binding domain for MSP and is constitutively active. In mouse breast cancer lung metastasis models, deletion of kinase activity from both isoforms of RON in the host nearly eradicates tumors through increased anti-tumor immunity. More recently, we identified SF-RON as the main isoform mediating tumor-associated immunity in these models, with loss of SF-RON promoting increased anti-tumor T cell activity. In the bone, loss of kinase activity from both isoforms of RON protects against bone loss, but its role in anti-tumor immunity is unknown. We now aim to delineate the role of SF-RON-mediated anti-tumor immune responses in the bone, where immunotherapy has been less effective. In SF-RON knockout mice (RonSF-/-), tumor cells injected into the bone grow for a short time but are undetectable by endpoint. Preliminary analyses suggest the importance of immune-mediated clearance in the loss of tumors in RonSF-/- mice as depletion of CD8+ T cells rescued tumor growth by approximately 50%. To gain insight into the role of immune cell populations in this anti-tumor response, we utilized immunohistochemistry and flow cytometry to characterize specific immune cells in bone metastasis. Initial results suggest increased infiltration of T cells, B cells, and NK cells into the tumors in the bones of RonSF-/- mice compared to wild-type controls. Notably, these immune cell populations are all known to play a significant role in the anti-tumor response in other models. Future work will utilize depletion studies to further investigate the role of T cells, B Cells, and NK cells in SF-RON-mediated tumor clearance in the bone. This work will help elucidate a role for host SF-RON in breast cancer bone metastasis and its potential to be a potent immunotherapy target for the treatment of bone metastasis.
Citation Format: Clint H Valencia, Jaime Fornetti, Alana L Welm. Defining the immune milieu in short-form RON-mediated tumor clearance in breast cancer bone metastasis [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A55.
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