Fructose Promotes Cytoprotection in Melanoma Tumors and Resistance to Immunotherapy.

Autor:	Kuehm LM; Saint Louis University School of Medicine, Molecular Microbiology and Immunology, St. Louis, Missouri., Khojandi N; Saint Louis University School of Medicine, Molecular Microbiology and Immunology, St. Louis, Missouri., Piening A; Saint Louis University School of Medicine, Molecular Microbiology and Immunology, St. Louis, Missouri., Klevorn LE; Saint Louis University School of Medicine, Molecular Microbiology and Immunology, St. Louis, Missouri., Geraud SC; Saint Louis University School of Medicine, Molecular Microbiology and Immunology, St. Louis, Missouri., McLaughlin NR; Saint Louis University School of Medicine, Molecular Microbiology and Immunology, St. Louis, Missouri., Griffett K; Saint Louis University School of Medicine, Pharmacological and Physiological Sciences, St. Louis, Missouri., Burris TP; Saint Louis University School of Medicine, Pharmacological and Physiological Sciences, St. Louis, Missouri., Pyles KD; Saint Louis University School of Medicine, Biochemistry and Molecular Biology, St. Louis, Missouri., Nelson AM; Webster University, Department of Biological Sciences, St. Louis, Missouri., Preuss ML; Webster University, Department of Biological Sciences, St. Louis, Missouri., Bockerstett KA; Saint Louis University School of Medicine, Molecular Microbiology and Immunology, St. Louis, Missouri., Donlin MJ; Saint Louis University School of Medicine, Biochemistry and Molecular Biology, St. Louis, Missouri., McCommis KS; Saint Louis University School of Medicine, Biochemistry and Molecular Biology, St. Louis, Missouri., DiPaolo RJ; Saint Louis University School of Medicine, Molecular Microbiology and Immunology, St. Louis, Missouri.; Alvin J. Siteman NCI Comprehensive Cancer Center, St. Louis, Missouri., Teague RM; Saint Louis University School of Medicine, Molecular Microbiology and Immunology, St. Louis, Missouri. ryan.teague@health.slu.edu.; Alvin J. Siteman NCI Comprehensive Cancer Center, St. Louis, Missouri.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2021 Feb; Vol. 9 (2), pp. 227-238. Date of Electronic Publication: 2020 Oct 06.
DOI:	10.1158/2326-6066.CIR-20-0396
Abstrakt:	Checkpoint blockade immunotherapy relies on the empowerment of the immune system to fight cancer. Why some patients fail to achieve durable clinical responses is not well understood, but unique individual factors such as diet, obesity, and related metabolic syndrome could play a role. The link between obesity and patient outcomes remains controversial and has been mired by conflicting reports and limited mechanistic insight. We addressed this in a C57BL/6 mouse model of diet-induced obesity using a Western diet high in both fats and sugars. Obese mice bearing B16 melanoma or MC38 carcinoma tumors had impaired immune responses to immunotherapy and a reduced capacity to control tumor progression. Unexpectedly, these compromised therapeutic outcomes were independent of body mass and, instead, were directly attributed to dietary fructose. Melanoma tumors in mice on the high-fructose diet were resistant to immunotherapy and showed increased expression of the cytoprotective enzyme heme oxygenase-1 (HO-1). This increase in HO-1 protein was recapitulated in human A375 melanoma cells exposed to fructose in culture. Induced expression of HO-1 shielded tumor cells from immune-mediated killing and was critical for resistance to checkpoint blockade immunotherapy, which could be overcome in vivo using a small-molecule inhibitor of HO-1. This study reveals dietary fructose as a driver of tumor immune evasion, identifying HO-1 expression as a mechanism of resistance and a promising molecular target for combination cancer immunotherapy. See article by Khojandi et al., p. 214 . (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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