Hyperglycemia enhances cancer immune evasion by inducing alternative macrophage polarization through increased O-GlcNAcylation

Rodrigues Mantuano, N.; Stanczak, M. A.; de Araujo Oliveira, I.; Kirchhammer, N.; Filardy, A.; Monaco, G.; Santos, R. C.; Carlos Fonseca, A.; Fontes, M.; de Souza Bastos, C.; Dias, W. B.; Zippelius, A.; Todeschini, A. R.; Laubli, H.

doi:10.1101/831610

bioRxiv · 10.1101/831610

Hyperglycemia enhances cancer immune evasion by inducing alternative macrophage polarization through increased O-GlcNAcylation

Rodrigues Mantuano, N.·Stanczak, M. A.·de Araujo Oliveira, I.·Kirchhammer, N.·Filardy, A.·Monaco, G.·Santos, R. C.·Carlos Fonseca, A.·Fontes, M.·de Souza Bastos, C.·Dias, W. B.·Zippelius, A.·Todeschini, A. R.·Laubli, H.

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Abstract

Diabetes mellitus (DM) significantly increases the risk for cancer and cancer progression. Hyperglycemia is the defining characteristic of DM and tightly correlates with a poor prognosis in cancer patients. The hexosamine biosynthetic pathway (HBP) is emerging as a pivotal cascade linking high glucose, tumor progression and impaired immune function. Here we show that enhanced glucose flow through the HBP drives cancer progression and immune evasion by increasing O-GlcNAcylation in tumor-associated macrophages (TAMs). Increased O-GlcNAc skewed macrophage polarization to a M2-like phenotype. HBP or O-GlcNAcylation inhibition reprogrammed TAMs to an anti-tumoral phenotype. Finally, we found an upregulation of M2 markers on TAMs in DM2 patients with colorectal cancer compared to non-diabetic normoglycemic patients. Our results provide evidence for a new and targetable mechanism of cancer immune evasion in patients with hyperglycemia, advocating for strict control of hyperglycemia in cancer patients.\n\nSignificanceHyperglycemia increases O-GlcNAc levels in TAMs, programing them to a pro-tumorigenic phenotype (M2-like), contributing to cancer progression. Inhibition of O-GlcNAcylation could therefore be used to reprogram intratumoral macrophages to an anti-tumoral phenotype.

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Rodrigues Mantuano, N., Stanczak, M. A., de Araujo Oliveira, I., Kirchhammer, N., Filardy, A., Monaco, G., Santos, R. C., Carlos Fonseca, A., Fontes, M., de Souza Bastos, C., Dias, W. B., Zippelius, A., Todeschini, A. R., Laubli, H.. 2019-11-05. Hyperglycemia enhances cancer immune evasion by inducing alternative macrophage polarization through increased O-GlcNAcylation. https://doi.org/10.1101/831610

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