Lyn Kinase Regulates Myeloid-Cell Responses to Mammary Tumors 2752

Abstract Description Myeloid-cell enrichment in tumors is correlated with increased metastasis, reduced survival times, and poor treatment outcomes in breast cancer. Many signals (CSF, Il-6, chemokine) to myeloid cells in the tumor microenvironment are transduced through the Src-family kinase Lyn, which is expressed as two isoforms: LynA and LynB. Total Lyn expression is negatively correlated with breast cancer patient survival, but the functional contributions of LynA and LynB in solid tumors have not been studied. In an E0771 orthotopic transplant model in hosts expressing or lacking LynA or LynB, we have discovered that Lyn expression in the mammary tumor microenvironment promotes the early recruitment of monocytes, macrophages, neutrophils, and dendritic cells, as determined by flow cytometry analysis of tumors early in development. Furthermore, Lyn promotes anti-inflammatory activation of tumor-associated macrophages. Tumors from Lyn knockout animals maintained WT-like numbers of inflammatory, anti-tumor macrophages, but the anti-inflammatory population was reduced. Together, our findings suggest that Lyn regulates the tumor-mediated chemotactic and inflammatory signaling response of myeloid cells, which are major factors in disease progression and treatment response. Modulation of Lyn activity, or the activity of its downstream signaling partners, is thus a potential strategy for manipulating the trafficking and anti-tumor activity of myeloid cells within breast tumors to benefit patients. Funding Sources Supported by American Cancer Society Kirby Foundation Postdoctoral Fellowship PF-21-068-01-LIB and NIH/NCI T32 CA009138. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)