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Targeting Alpha-Ketoglutarate Disruption Overcomes Immunoevasion and Improves PD-1 Blockade Immunotherapy in Renal Cell Carcinoma.

ABSTRACT: The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation-induced immunoevasion as a crucial contributor. In this study, a significant decrease is found in the abundance of alpha-ketoglutarate (αKG), a crucial intermediate metabolite in the TCA cycle, which is correlated with higher grades and a worse prognosis in clinical RCC samples. Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of β2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti-tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC.

SUBMITTER: Li L

PROVIDER: S-EPMC10520657 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Targeting Alpha-Ketoglutarate Disruption Overcomes Immunoevasion and Improves PD-1 Blockade Immunotherapy in Renal Cell Carcinoma.

Li Le L Zeng Xing X Chao Zheng Z Luo Jing J Guan Wei W Zhang Qiang Q Ge Yue Y Wang Yanan Y Xiong Zezhong Z Ma Sheng S Zhou Qiang Q Zhang Junbiao J Tian Jihua J Horne David D Yuh Bertram B Hu Zhiquan Z Wei Gong-Hong GH Wang Baojun B Zhang Xu X Lan Peixiang P Wang Zhihua Z

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230801 27

The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation-induced immuno ...[more]

PMID: 37526345

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Project description:PurposeLimited treatment options exist for refractory ovarian cancer (OC) due to its poor response to immune therapies. Therefore, there is an urgent need to develop new effective treatment strategies. Chicoric acid (CA) is reported to have immune-enhancing properties, but its efficacy in cancer treatment is not well understood. We hypothesize that CA might improve the efficacy of PD-1/PD-L1 blockade immunotherapy in refractory OC patients.MethodsPatient-derived xenograft (PDX) models were constructed from chemoresistant advanced high-grade serous ovarian cancer patients. These models were treated with CA, aPD-1/aPD-L1 antibodies, or a combination of both. Single-cell RNA sequencing was performed to analyze the cellular composition of the tumor microenvironment (TME), evaluate treatment efficacy, and explore therapeutic mechanisms. Variations in peripheral blood lymphocytes were analyzed via fluorescence-activated cell sorting. Immunohistochemistry confirmed the variations in tumor-infiltrating lymphocytes and tumor cells.ResultsImmunocompetent peripheral blood mononuclear cell (PBMC)-PDX models were successfully constructed using malignant ascites fluid and PBMCs. After treatment, 158,734 cells from 15 samples were categorized into epithelial cells, T lymphocytes, myeloid cells, fibroblasts, and endothelial cells. CA enhanced the antitumor ability of immune cells against OC cells. Notably, CA stimulated the proliferation of CD45 + and CD3 + cells and promoted the migration of CD8 + and CD4 + T cells from peripheral blood to infiltrate the TME. Additionally, CA enhanced the response of OCs to aPD-L1/aPD-1 treatment, strengthened the interaction between tumor and nontumor cells, and identified APP/CD74 as a critical ligand‒receptor pair. CHI3L1 was also found to be a potential marker for predicting immunotherapy efficacy in OC.ConclusionThis study demonstrated that combination therapy with CA and aPD-1/aPD-L1 might be a promising strategy for treating OC effectively.

Dataset Information

Targeting Alpha-Ketoglutarate Disruption Overcomes Immunoevasion and Improves PD-1 Blockade Immunotherapy in Renal Cell Carcinoma.

Publications

Targeting Alpha-Ketoglutarate Disruption Overcomes Immunoevasion and Improves PD-1 Blockade Immunotherapy in Renal Cell Carcinoma.

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