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.
Highlights
The tumor microenvironment (TME) provides the interface for communication between malignant and immune cells
Because maximal tumor associated macrophages (TAMs) infiltration to mammary glands and tumors of polyomavirus middle T-antigen (PyMT) mice is observed at 12 weeks[17], mice were euthanized after 8 weeks on diet, and mammary glands and tumors were analyzed by multicolor flow cytometry
In accordance with in vitro findings, we showed that CDDO-methyl ester (CDDO-Me) reprograms breast TAMs in vivo from tumor-promoting to tumor-inhibiting as determined by surface phenotype, cytokine production, and transcriptional profile
Summary
The tumor microenvironment (TME) provides the interface for communication between malignant and immune cells. High TAM volumes are associated with poor clinical outcome for several solid tumor types, including cancer of the breast, bladder, prostate, cervix, and ovary[9,10]. Because these cells support tumor growth, progression and metastatic potential, TAMs are an attractive therapeutic target. CDDO-Me increases the ratio of CD8+:CD4+ T cells in tumors, and in the spleen, CD8+ T cell numbers are enhanced concurrent with decreases in CD4+ T cells These results demonstrate for the first time the in vivo immunological effect of CDDO-Me on the breast TME and implicate TAMs as potential effectors of drug response through repolarization
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