c-Myb upregulation stimulates antitumor immunity in a murine colorectal cancer model
While the transcription factor c-Myb is overexpressed in different types of solid tumors, including colorectal cancer, its exact role in tumorigenesis is unclear. In this study, we show that tumor-intrinsic c-Myb expression in mouse models of colon cancer and melanoma suppresses tumor growth. While no difference in proliferation, apoptosis, and angiogenesis of tumors were evident, we observed changes in intratumoral immune cell infiltrates. MC38 tumors with upregulated c-Myb expression showed increased counts of CD103+ dendritic cells and eosinophils, but decreased tumor-associated macrophages (TAMs). Concomitantly, an increase in cytotoxic CD8+ T cells upon c-Myb upregulation was observed, which correlated with a pro-inflammatory tumor microenvironment and increased numbers of M1 polarized TAMs. Mechanistically, c-Myb upregulation in immunogenic MC38 colon cancer cells resulted in enhanced expression of immunomodulatory genes, including b2-microglobulin, interferon-ß and decreased expression of the chemokine receptor CCR2. The observed increased counts of cytotoxic CD8+ T cells contributed to tumor growth attenuation. In poorly immunogenic CT26, LLC and B16-BL6 tumor cells, c-Myb upregulation did not affect immune responses. Interestingly, c-Myb upregulation has led to a reduced B16-BL6 tumor growth but it did not affect tumor growth of CT26 and LLC tumors. Altogether, we postulate that c-Myb functions as a tumor suppressor in a tumor cell-type specific manner and modulates anti-tumor immunity. Overall design: MC38T/O (doxycycline inducible c-Myb, 5x105 cells) tumor cells were subcutaneously injected in the right flank of a mouse. Mice were fed doxycycline containing or control chow for 21 days. GFP+CD45- tumor cells were sorted from excized tumors and RNA was isolated using RNeasy Plus Mini Kit (Qiagen). RNAseq of DOX-treated (c-Myb induced expression) and control tumor cells was analyzed.