HUNK as an Immune Regulator of Triple Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Unlike other breast cancer types, TNBC tumors do not respond to endocrine therapy, and standardized treatment protocols for TNBC are currently unavailable. TNBC is recognized as a more metastatic, aggressive, and immunogenic subtype of breast cancer, rendering it to be more receptive to immunotherapy. Among the immune cell populations abundant in TNBC tumors, tumor-associated macrophages (TAMs) are particularly more prevalent and are particularly known to play a role in cancer metastasis. This work focuses on and investigates the involvement of the protein kinase HUNK in tumor immunity. With the use of gene expression analysis, such as NanoString's nCounter PanCancer Immune Profiling panel, we found that targeting HUNK is associated with alterations in the IL-4/IL-4R cytokine signaling pathway. Experimental analysis and work demonstrated that HUNK kinase activity regulates IL-4 production in mammary tumor cells, and this regulation is dependent on STAT3. Furthermore, in vivo, analysis shows that HUNK-dependent control of IL-4 secretion from tumor cells leads to the polarization of macrophages into an M2-like phenotype, and consequently, IL-4 induction promotes cancer metastasis and prompts macrophage's metastatic capacities. These findings underscore HUNK as a potential therapeutic target for mitigating TNBC metastasis by modulating the TAM population.