Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma
Kang Sun, Xiaozhen Zhang, Jiatao Shi, Jinyan Huang, Sicheng Wang, Xiang Li, Haixiang Lin, Danyang Zhao, Mao Ye, Sirui Zhang, Li Qiu, Minqi Yang, Chuyang Liao, Lihong He, Mengyi Lao, Jinyuan Song, Na Lu, Yongtao Ji, Hanshen Yang, Lingyue Liu, Xinyuan Liu, Yan Chen, Shicheng Yao, Qianhe Xu, Jieru Lin, Yan Mao, Jingxing Zhou, Xiao Zhi, Ke Sun, Xiongbin Lu, Xueli Bai, Tingbo Liang
Kang Sun, Xiaozhen Zhang, Jiatao Shi, Jinyan Huang, Sicheng Wang, Xiang Li, Haixiang Lin, Danyang Zhao, Mao Ye, Sirui Zhang, Li Qiu, Minqi Yang, Chuyang Liao, Lihong He, Mengyi Lao, Jinyuan Song, Na Lu, Yongtao Ji, Hanshen Yang, Lingyue Liu, Xinyuan Liu, Yan Chen, Shicheng Yao, Qianhe Xu, Jieru Lin, Yan Mao, Jingxing Zhou, Xiao Zhi, Ke Sun, Xiongbin Lu, Xueli Bai, Tingbo Liang
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Research Article Immunology Oncology

Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma

Abstract

Metabolic reprogramming shapes the tumor microenvironment (TME) and may lead to immunotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Elucidating the impact of pancreatic cancer cell metabolism in the TME is essential to therapeutic interventions. “Immune cold” PDAC is characterized by elevated lactate levels resulting from tumor cell metabolism, abundance of protumor macrophages, and reduced cytotoxic T cells in the TME. Analysis of fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in patients showed that increased global protein lactylation in PDAC correlates with worse clinical outcomes in immunotherapy. Inhibition of lactate production in pancreatic tumors via glycolysis or mutant-KRAS inhibition reshaped the TME, thereby increasing their sensitivity to immune checkpoint blockade (ICB) therapy. In pancreatic tumor cells, lactate induces K63 lactylation of endosulfine α (ENSA-K63la), a crucial step that triggers STAT3/CCL2 signaling. Consequently, elevated CCL2 secreted by tumor cells facilitates tumor-associated macrophage (TAM) recruitment to the TME. High levels of lactate also drive transcriptional reprogramming in TAMs via ENSA-STAT3 signaling, promoting an immunosuppressive environment. Targeting ENSA-K63la or CCL2 enhances the efficacy of ICB therapy in murine and humanized pancreatic tumor models. In conclusion, elevated lactylation reshapes the TME and promotes immunotherapy resistance in PDAC. A therapeutic approach targeting ENSA-K63la or CCL2 has shown promise in sensitizing pancreatic cancer immunotherapy.

Authors

Kang Sun, Xiaozhen Zhang, Jiatao Shi, Jinyan Huang, Sicheng Wang, Xiang Li, Haixiang Lin, Danyang Zhao, Mao Ye, Sirui Zhang, Li Qiu, Minqi Yang, Chuyang Liao, Lihong He, Mengyi Lao, Jinyuan Song, Na Lu, Yongtao Ji, Hanshen Yang, Lingyue Liu, Xinyuan Liu, Yan Chen, Shicheng Yao, Qianhe Xu, Jieru Lin, Yan Mao, Jingxing Zhou, Xiao Zhi, Ke Sun, Xiongbin Lu, Xueli Bai, Tingbo Liang

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Figure 1

Elevated lactylation is correlated with immunosuppressive TME in PDAC.

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Elevated lactylation is correlated with immunosuppressive TME in PDAC. (...
(A) Representative images of mIHC staining in paracancerous (Para) and tumor tissues. Paracancerous and tumor tissues on tissue microarray were stained. Scale bar: 0.1 cm. (B) Expression differences of indicated genes between paracancerous and tumor tissues. Histochemistry score (h-score) was used to measure the expression of these genes in each region. Intact tissues were included in follow-up analysis. Statistical analyses were performed with the paired sample t test (41 pairs). (C) Correlation analysis between SLC2A1, HK2, LDHA, SLC16A3, and Pan-Kla levels. Forty-one pairs of paracancerous and tumor tissues were included in the analysis. H-score was used to measure the expression of these genes in each region and then perform Pearson’s correlation analysis (n = 82). (D) Kaplan-Meier survival curves of overall survival (OS) for patients with PDAC in an in-house TMA. TMAs were stained using anti–Pan-Kla antibodies. Patients were divided into 2 groups according to median amount of h-score. Intact tumor tissues with survival data were included in follow-up analysis. Statistical analyses were performed with log-rank test (n = 116). (E) Twenty fresh pancreatic tumor samples were processed into a single-cell suspension and flow cytometry was performed using Cytek. Samples were divided into 2 groups according to Pan-Kla expression. Statistical analyses were performed with Student’s t test (n = 20). (F) Representative images and statistical chart of mIHC staining of pancreatic cancer samples. TMAs of 140 pancreatic cancer samples were stained. Intact tissues were included in follow-up analysis. Samples were divided into 2 groups according to h-score of Pan-Kla. Proportion of each cell type in total cells was calculated. Statistical analyses were performed with Student’s t test (n = 140). Scale bar: 0.1 cm. (G) Pan-Kla expression and 2-NBDG uptake tested using flow cytometry by each cell type in human paired tumors and peripheral blood. (H and I) Gene ontology enrichment analysis of macrophages (H) and CD8+ T cells (I). *P < 0.05; **P < 0.01; ****P < 0.0001.