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Increased tumor glycolysis is associated with decreased immune infiltration across human solid tumors.

ABSTRACT: Response to immunotherapy across multiple cancer types is approximately 25%, with some tumor types showing increased response rates compared to others (i.e. response rates in melanoma and non-small cell lung cancer (NSCLC) are typically 30-60%). Patients whose tumors are resistant to immunotherapy often lack high levels of pre-existing inflammation in the tumor microenvironment. Increased tumor glycolysis, acting through glucose deprivation and lactic acid accumulation, has been shown to have pleiotropic immune suppressive effects using in-vitro and in-vivo models of disease. To determine whether the immune suppressive effect of tumor glycolysis is observed across human solid tumors, we analyzed glycolytic and immune gene expression patterns in multiple solid malignancies. We found that increased expression of a glycolytic signature was associated with decreased immune infiltration and a more aggressive disease across multiple tumor types. Radiologic and pathologic analysis of untreated estrogen receptor (ER)-negative breast cancers corroborated these observations, and demonstrated that protein expression of glycolytic enzymes correlates positively with glucose uptake and negatively with infiltration of CD3⁺ and CD8⁺ lymphocytes. This study reveals an inverse relationship between tumor glycolysis and immune infiltration in a large cohort of multiple solid tumor types.

SUBMITTER: Cohen IJ

PROVIDER: S-EPMC9731115 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Increased tumor glycolysis is associated with decreased immune infiltration across human solid tumors.

Cohen Ivan J IJ Pareja Fresia F Socci Nicholas D ND Shen Ronglai R Doane Ashley S AS Schwartz Jazmin J Khanin Raya R Morris Elizabeth A EA Sutton Elizabeth J EJ Blasberg Ronald G RG

Frontiers in immunology 20221124

Response to immunotherapy across multiple cancer types is approximately 25%, with some tumor types showing increased response rates compared to others (i.e. response rates in melanoma and non-small cell lung cancer (NSCLC) are typically 30-60%). Patients whose tumors are resistant to immunotherapy often lack high levels of pre-existing inflammation in the tumor microenvironment. Increased tumor glycolysis, acting through glucose deprivation and lactic acid accumulation, has been shown to have pl ...[more]

PMID: 36505421

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Project description:BackgroundPrior studies showed that tumor glycolysis and tumor immune evasion are interdependent. However, a systematic investigation of the association between tumor glycolysis and tumor immunity in various cancers remains lacking.MethodsUsing the Cancer Genome Atlas (TCGA) datasets, we explored the association between glycolytic activity and immune signatures in 14 cancer types. We also explored the associations between glycolytic activity and tumor immunity associated genetic features, including PD-L1 expression, tumor mutation burden (TMB), and tumor aneuploidy. Moreover, we performed in vitro experiments to verify some findings from bioinformatics analysis. Furthermore, we explored the association between tumor glycolytic activity and immunotherapy response.FindingsGlycolytic activity was likely correlated with active immune signatures in various cancers and highly glycolytic tumors presented an immune-stimulatory tumor microenvironment. Compared to TMB and aneuploidy, glycolytic activity was a stronger and more consistent predictor for immune signatures in diverse cancers. Both computational and experimental analyses showed that glycolysis could increase PD-L1 expression in tumor. Glycolytic activity had a strong correlation with apoptosis which was a strong positive predictor for immune signatures, suggesting that apoptosis could be an important medium connecting glycolytic activity with immune activity in cancer. Finally, highly glycolytic tumors exhibited a better immunotherapy response and a favorable survival in the immunotherapy setting.InterpretationTumor glycolysis may increase tumor immunity in diverse cancers. Glycolytic activity enhances PD-L1 expression on tumor cells and thus promotes anti-PD-1/PD-L1 immunotherapy response. Thus, the tumor glycolytic activity could be a predictive biomarker for immunotherapy response in diverse cancers. FUND: This work was supported by the China Pharmaceutical University (grant numbers 3150120001, 2632018YX01 to XW).

Dataset Information

Increased tumor glycolysis is associated with decreased immune infiltration across human solid tumors.

Publications

Increased tumor glycolysis is associated with decreased immune infiltration across human solid tumors.

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