Tumor cell intrinsic RON signaling suppresses innate immune responses in breast cancer through inhibition of IRAK4 signaling

• Published in: Cancer letters Vol. 503; pp. 75 - 90
• Main Authors: Bourn, Jennifer R., Ruiz-Torres, Sasha J., Hunt, Brian G., Benight, Nancy M., Waltz, Susan E.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 10.04.2021; Elsevier Limited
• Subjects: Animals; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; CD8 antigen; Cell growth; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytokines; Cytotoxicity; Female; Gene Expression Regulation, Neoplastic; Humans; Immunity, Innate; Immunotherapy; Innate immunity; Interferon; Interleukin-1 Receptor-Associated Kinases - metabolism; IRAK4 regulation; Kinases; Laboratories; Lymphocytes T; Macrophages; MCF-7 Cells; Metastases; Metastasis; Mice; Molecular modelling; Natural killer cells; Neoplasm Transplantation; Phenotypes; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Receptor tyrosine kinases; Rodents; Ron protein; Signal Transduction; Tumor cells; Tumor Microenvironment; Tumors; Type I IFN signaling; United States > US; Type I IFN signaling; Breast cancer; Tumor microenvironment; Receptor tyrosine kinases; IRAK4 regulation
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.01.019

Increasing evidence suggests that cancer cells require both alterations in intrinsic cellular processes and the tumor microenvironment for tumor establishment, growth, and progression to metastatic disease. Despite this, knowledge of tumor-cell intrinsic molecular mechanisms controlling both tumor cell processes as well as the tumor microenvironment is limited. In this study, we provide evidence demonstrating the novel role of RON signaling in regulating breast cancer initiation, progression, and metastasis through modulation of tumor cell intrinsic processes and the tumor microenvironment. Using clinically relevant models of breast cancer, we show that RON signaling in the mammary epithelial tumor cells promotes tumor cell survival and proliferation as well as an immunopermissive microenvironment associated with decreased M1 macrophage, natural killer (NK) cell, and CD8+ T cell recruitment. Moreover, we demonstrate that RON signaling supports these phenotypes through novel mechanisms involving suppression of IRAK4 signaling and inhibition of type I Interferons. Our studies indicate that activation of RON signaling within breast cancer cells promotes tumor cell intrinsic growth and immune evasion which support breast cancer progression and highlight the role of targeting RON signaling as a potential therapeutic strategy against breast cancer. •RON expression promotes mammary tumor development, growth, and metastasis in breast cancer mouse models.•RON expression supports a pro-tumor microenvironment and protection from immune cell attack.•Tumor cell intrinsic RON signaling promotes cell proliferation, inhibits apoptosis, and suppresses type I IFNs in breast cancer cells.•RON-mediated suppression of type I IFNs production is dependent on the direct interaction of RON and IRAK4.•Blocking Ron in combination with immunotherapy may represent a novel approach to combat breast cancer.