Heat shock factor 1 determines the phenotype of tumor associated macrophages

Heat shock factor-1 (HSF-1) is an important regulator of oncogenes, affecting both pathogenesis and prognosis of human cancer. However, it is not currently known how HSF-1 can modulate immune response in cancer progression. In the present work, using mouse B-cell lymphoma tumor model, we report that HSF-1 ablation ( +/- or -/- ) of hosts enhances pro-inflammatory response by altering macrophage phenotypes at tumor site, and it inhibits lymphoma tumor xenograft growth. Even though high abundance of tumor-associated macrophages (TAMs) and increased CCl2 in peripheral circulation were found in HSF-1 -/- hosts, CD31+ expression was low in these tumors indicating reduced angiogenesis. Furthermore, in HSF-1 -/- mice grown tumors, TAMs showed very low CD206+ mannose receptor (MR), which is a hallmark of alternatively activated macrophages (M2) phenotype, expression suggesting that TAMs, present in HSF-1 -/- hosts tumor microenvironment, exhibit pro-inflammatory M1 phenotype. Also, an increased plasma level IL-6 and IgA, higher cytotoxic CD8+ T cells in spleenocytes, and higher IFN-g were observed in tumor bearing HSF-1 -/- mice. Our in-vitro assay indicated that addition of HSF-1 -/- sera induced caspase-independent lymphoma tumor cell death (involving a distinct 55kD PARP-1 catalytic domain cleavage and 75kD fragment in TOPO I) and increased lysosomal enzyme activity, as measured by CD40L in tumor bearing HSF-1 -/- mice plasma. Taken together, our results establish that HSF-1 is a critical determinant in TAM polarization and tumor immunity, and its repression could enhance innate immunity and immune surveillance against lymphoma tumor growth. Therefore, HSF-1 is a major determinant in TAM polarization, and it is a potential target for lymphoma treatment.