Loss of short-form Ron promotes B and T cell cooperation to prevent outgrowth of breast cancer bone metastasis

While immunotherapy has great potential to eradicate tumors, success in metastatic breast cancer is limited. Bone metastasis, the most common site for breast cancer metastasis, has been associated with weakened anti-tumor immunity, both in the bone and in other metastatic sites. Additional strategies promoting anti-tumor immunity are needed. Using the MMTV-PyMT intratibial model of breast cancer bone metastasis, we discovered that deletion of host short-form Ron (Ron SF-/-) protected against bone metastatic outgrowth by promoting strong infiltration of lymphocytes, including B cells, into tumors at the micrometastasis stage. Transcriptionally, Ron SF-/- B cells were more active and inflammatory compared to wildtype. Elimination of mature B cells (JH-/-) rescued tumor growth in Ron SF-/- mice, indicating that mature B cells were necessary for anti-tumor immunity and protection against bone metastasis. In Ron SF-/- hosts, T follicular helper (Tfh) cells were abundant in tumor-enriched regions of bone, suggesting interactions between B and T cells. B-T cell cooperation was further supported by attenuation of CD4 and CD8 T cell tumor infiltration in Ron SF-/-JH-/- hosts and, conversely, diminished B cell tumor infiltration and rescue of tumor growth in Ron SF-/- hosts lacking CD4 or CD8 T cells. B cells were not required to protect Ron SF-/- mice from lung metastasis, indicating a tissue-dependent anti-tumor role for B cells. These data support a positive feedback loop between B and T cells regulated by SF-Ron and reveal the anti-tumor potential of B cells in the bone.