CDDO-Me Alters the Tumor Microenvironment in Estrogen Receptor Negative Breast Cancer
Michael Ball, Rajan Bhandari, Gretel M. Torres, Viktor Martyanov, Mohamed ElTanbouly, Kim Archambault, Michael L. Whitfield, Karen T. Liby, Patricia A. Pioli
Abstract
Abstract The tumor microenvironment (TME) is an essential contributor to the development and progression of malignancy. Within the TME, tumor associated macrophages (TAMs) mediate angiogenesis, metastasis, and immunosuppression, which inhibits infiltration of tumor-specific cytotoxic CD8+ T cells. In previous work, we demonstrated that the synthetic triterpenoid CDDO-methyl ester (CDDO-Me) converts breast TAMs from a tumor-promoting to a tumor-inhibiting activation state in vitro . We show now that CDDO-Me remodels the breast TME, redirecting TAM activation and T cell tumor infiltration in vivo . We demonstrate that CDDO-Me significantly attenuates IL-10 and VEGF expression but stimulates TNF production, and reduces surface expression of CD206 and CD115, markers of immunosuppressive TAMs. CDDO-Me treatment redirects the TAM transcriptional profile, inducing signaling pathways associated with immune stimulation, and inhibits TAM tumor infiltration, consistent with decreased expression of CCL2. In CDDO-Me-treated mice, both the absolute number and proportion of splenic CD4 + T cells were reduced, while the proportion of CD8 + T cells was significantly increased in both tumors and spleen. Moreover, mice fed CDDO-Me demonstrated significant reductions in numbers of CD4 + Foxp3 + regulatory T cells within tumors. These results demonstrate for the first time that CDDO-Me relieves immunosuppression in the breast TME and unleashes host adaptive anti-tumor immunity.