Epidemiological studies have shown diabetes mellitus (DM) to significantly increase the risk for cancer and cancer progression. Hyperglycemia is the most important characteristic of DM and directly correlates with a poor prognosis in cancer patients. While enhanced availability of glucose can directly fuel tumor cell proliferation, the effect on the tumor immune microenvironment is less well known. Here, we demonstrate in vitro and in different murine tumor models that hyperglycemia induces an increased flux through the hexosamine biosynthetic pathway (HBP) in tumor-associated macrophages (TAMs) resulting in an upregulation of O-GlcNAcylation. Increased O-GlcNAcylation was associated with alternative M2 polarization of TAMs and reduced anti-tumor immunity. The effect of hyperglycemia on tumor growth was dependent on an intact adaptive immunity. Furthermore, inhibition of M2 polarization by the addition of anti-CSF1R antibodies abrogated the effect of hyperglycemia on tumor growth. Similarly, treatment of mice with inhibitors of the HBP or O-GlcNAcylation reduced M2 polarization of TAMs and reversed immune evasion of growing tumors. Finally, we find enhanced M2 polarization in chronically hyperglycemic patients with colorectal cancer compared to non-diabetic normoglycemic patients. Our findings provide a new and targetable mechanism of cancer immune evasion, advocating for strict control of hyperglycemia in cancer patients.

Citation Format: Natalia Rodrigues Mantuano, Michal Stanczak, Isadora Oliveira, Alessandra Filardy, Ronan Silva, Alfred Zippelius, Adriane Regina Todeschini, Heinz Laubli. Hyperglycemia enhances cancer immune evasion by inducing alternative macrophage polarization through increased O-GlcNAcylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-059.