Abstract
Purpose
Immunotherapy with programmed cell death 1/ligand 1 (PD-1/PD-L1) checkpoint inhibitors has revolutionized the systemic treatment of solid tumors, including bladder cancer. Previous studies have shown that enhanced glycolysis, tumor-associated macrophage (TAM) infiltration, and TGF-β secretion in the tumor microenvironment (TME) are closely related to PD-1/PD-L1 inhibitor immunotherapy resistance. However, the potential mechanism of their interaction in bladder cancer has not been fully uncovered.
Methods
By coculturing bladder cancer cells and TAMs, we studied the relationship and interaction mechanism between tumor cell glycolysis, TAM functional remodeling, TGF-β positive feedback secretion, and PD-L1 mRNA m6A methylation in the bladder cancer microenvironment.
Results
Bioinformatics analysis and IHC staining found a close correlation between tumor glycolysis, M2 TAM infiltration, and the prognosis of bladder cancer patients. In Vitro experiments demonstrated that bladder cancer cells could re-educate M2 TAMs through lactate and promote TGF-β secretion via the HIF-1α signaling pathway. Reciprocally, in vitro, and in vivo experiments validated that M2 TAMs could promote glycolysis in bladder cancer cells by TGF-β via the Smad2/3 signaling pathways. Furthermore, M2 TAMs could also promote CSCs and EMT of bladder cancer cells. More importantly, we found M2 TAMs enhance PD-L1 mRNA m6A methylation by promoting METLL3 expression in bladder cancer via the TGF-β/Smad2/3 pathway in the TME.
Conclusions
Our study highlights a feed-forward loop based on aerobic glycolysis and TGF-β between M2 TAMs and bladder cancer cells, which may be a potential mechanism of malignant progression and immunotherapy resistance in bladder cancer.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
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Funding
This work was supported by the National Natural Science Foundation of China (No. 81972378, 81101932).
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CS wrote the main manuscript text. JiL and WJ validated data. XZ and XZ was analyzed data by software. XY and YW reviewed and edited. All authors reviewed the manuscript.
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432_2023_5164_MOESM1_ESM.tif
Supplementary 1. (A) The TCGA and GEO bladder cancer cohorts were divided into three clusters when k = 3. (B) Consensus clustering cumulative distribution function (CDK) fork = 2 to 9. (C) Relative change in area under the CDF curve for k = 2 to 9. (D) The difference in the immune cell infiltration among three glycolysis clusters by using the CIBERSORT dataset. (E, F) The difference in the cytokine-related gene expression among three glycolysis clusters by using TCGA and GEO bladder cancer cohorts. (G) The experimental scheme along with the treatment protocol (TIF 17857 KB)
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Shen, C., Liu, J., Jiao, W. et al. A feed-forward loop based on aerobic glycolysis and TGF-β between tumor-associated macrophages and bladder cancer cells promoted malignant progression and immune escape. J Cancer Res Clin Oncol 149, 12867–12880 (2023). https://doi.org/10.1007/s00432-023-05164-5
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DOI: https://doi.org/10.1007/s00432-023-05164-5