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Fructose Promotes Cytoprotection in Melanoma Tumors and Resistance to Immunotherapy.

ABSTRACT: 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.

SUBMITTER: Kuehm LM

PROVIDER: S-EPMC7864871 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Fructose Promotes Cytoprotection in Melanoma Tumors and Resistance to Immunotherapy.

Kuehm Lindsey M LM Khojandi Niloufar N Piening Alexander A Klevorn Lauryn E LE Geraud Simone C SC McLaughlin Nicole R NR Griffett Kristine K Burris Thomas P TP Pyles Kelly D KD Nelson Afton M AM Preuss Mary L ML Bockerstett Kevin A KA Donlin Maureen J MJ McCommis Kyle S KS DiPaolo Richard J RJ Teague Ryan M RM

Cancer immunology research 20201006 2

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 usin ...[more]

PMID: 33023966

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Project description:Background: IκBζ, a rather unknown co-regulator of NF-κB, is mostly inducibly expressed and can either activate or repress a specific subset of NF-κB target genes. While its role as a transcriptional regulator of various cytokines and chemokines in immune cells has been revealed, IκBζ’s function in solid cancer remains unclear. Methods: We investigated IκBζ expression in melanoma, and assessed its impact on target gene expression, tumor growth, and response to immunotherapy in melanoma cell lines, mouse models, and patient samples. Results: Unlike in other cell types, IκBζ protein was found to be constitutively expressed in a subfraction of melanoma cell lines, and around 35% of melanoma cases. This atypical expression pattern of IκBζ did not correlate with its mRNA levels or known driver mutations, but instead seemed to result from changes in its post-transcriptional or post-translational regulation. Deleting constitutively expressed IκBζ abrogated the activity and chromatin association of STAT3 and p65, leading to reduced expression of the pro-proliferative cytokines IL-1β and IL-6 in melanoma cells. Consequently, loss of tumor-derived IκBζ suppressed self-sustained melanoma cell growth both in vitro and in vivo. Additionally, constitutive IκBζ expression suppressed the induction of the chemokines CXCL9, CXCL10, and CCL5, which impaired the recruitment of NK and CD8+ T-cells to the tumor, causing resistance to α-PD-1 immunotherapy in mice. Furthermore, the expression of tumor-derived IκBζ also correlated with the absence of CD8+ T-cells in human melanoma samples and progressive disease during immunotherapy. Conclusion: We propose that tumor-derived IκBζ could serve as a new therapeutic target and prognostic marker that characterizes melanoma with high tumor cell proliferation, cytotoxic T- and NK-cell exclusion, and unfavorable immunotherapy responses. Targeting IκBζ expression might open up a new therapy option to re-establish the recruitment of cytotoxic cells, thereby resensitizing for immunotherapy.

Dataset Information

Fructose Promotes Cytoprotection in Melanoma Tumors and Resistance to Immunotherapy.

Publications

Fructose Promotes Cytoprotection in Melanoma Tumors and Resistance to Immunotherapy.

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