Macrophage - T cell interactions regulate anti-tumor immunity 2215

Description Breast cancer (BRCA) is the second leading cause of cancer-related mortality in women. While cancer immunotherapy shows promise in treating some solid tumors, its effectiveness in BRCA remains limited. High levels of CD8+ T cells, which are key targets in immunotherapy, correlate with positive responses in BRCA, especially in aggressive cases like triple-negative BRCA. However, prolonged exposure to the tumor microenvironment (TME) drives CD8+ T cells to terminal functional exhaustion, reducing immunotherapy efficacy. The mechanisms by which the TME induces this dysfunction in T cells are not fully understood. BRCA tumors are densely infiltrated by tumor-associated macrophages (TAMs), which are linked to poorer patient outcomes. In our previous work, we observed a spatiotemporal co-dependency between exhausted T cells (TEX) and TAMs, wherein TEX attract monocytes into the TME, shaping their differentiation into TAMs. TAMs, in turn, engage in long-lasting interactions with T cells to promote exhaustion. Nonetheless, the molecular mechanism by which TAMs interact with T cells in the BRCA TME to drive exhaustion remains unclear. We propose that TAMs and TEX communicate through chemokine signaling pathways, suppressing anti-tumor immunity. This research aims to uncover new strategies for reprogramming TAMs to reduce CD8+ T cell exhaustion, ultimately enhancing the immunotherapy outcomes for BRCA patients.