Friday, May 9, 2025
5/9/2025
Tumor cell -TAM Paracrine Signaling in Breast Cancer - ABSTRACT Immune checkpoint inhibitors are FDA approved for metastatic triple negative breast cancer (TNBC) and work well for patients with high levels of tumor infiltrating lymphocytes (TIL), but for the majority of BC patients, these agents are ineffective. Continued research is needed to elucidate the interplay between tumor cells and the diverse immune cell populations within the primary TME, and how this interaction shapes tumor biology. Tumor- associated macrophages (TAM) represent one of the most abundant immune components in BC TME and exhibit a robust and unique influence on the disease. High levels of TAM infiltration are associated with poor prognosis in BC. TAMs play a critical role in a wide range of pro-tumorigenic, pro-metastatic activities including tumor angiogenesis, extracellular matrix (ECM) remodeling, immunosuppression, and chemoresistance. How to surmount TAM infiltration and function in order to activate a potent anti-tumorigenic and anti-metastatic response represents a gap in knowledge for the BC field. TAMs most closely resemble M2-polarized type macrophages and exhibit some overlapping functions between the categories. TAMs are a highly heterogeneic, plastic cell population endowed with tumor-promoting functionality measured by the overall abundance of M2 vs M1 markers. TAM polarization and immunosuppressive capacities are dependent upon where these cells are located and what signals are received within the TME. Whereas M2-like polarization is considered pro-tumorigenic, M1- like polarization is associated with inflammatory, anti-tumor effects and improved prognosis. Tumor cells generate paracrine signals that recruit and regulate TAM function. In turn, TAMs produce signals that affect the metastatic potential of tumor cells. Given the clear pro-tumor and metastatic roles of TAMs, it seems evident that identifying ways to abrogate pro-tumorigenic M2-like responses and promote anti-tumorigenic M1-like responses in BC will be clinically advantageous. However, effective strategies remain elusive. Our proposal introduces a new strategy to target a kinase called HUNK that has the potential to be more advantageous than strategies that directly target TAMs. Targeting HUNK will have a multifaceted effect by not only halting pro-tumor/metastatic tumor intrinsic signaling but also fundamentally changing the “feed forward” paracrine loop between tumor cells and TAMs.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).