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 6

Lactate accumulation reprograms TAMs by ENSA lactylation.

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Lactate accumulation reprograms TAMs by ENSA lactylation. (A) Pan-Kla an...
(A) Pan-Kla and p-STAT3 expression were tested using intracellular flow cytometry in each cell type from Hk2-NC and Hk2-KD KPC orthotopic tumors. (B) Protein expression analysis of BMDMs pretreated with Hk2-NC and Hk2-KD KPC cell supernatant and then treated with NALA (10 mM, 24 hours). (C) Protein expression analysis of BMDMs pretreated with KPC cell supernatant (1:1, 24 hours) and then treated with K63la-pe control 3 or K63-pe inhibitor 3 (10 μM, 24 hours). (D) BMDMs were pretreated with KPC supernatant (1:1, 24 hours) and then treated with NALA (40 mM, 24 hours). Relative Ccl2, Arg1, S100A9, and Il10 mRNA expression levels are shown. (E) CCL2, IL10, ARG1, and S100A9 expression in TAMs. Flow cytometry was used. Statistical analyses were performed with Student’s t test (n = 5). (F) Representative images of mIHC staining of KTC tumor samples from transgenic mice (LSL-Kras [G12D/+]; Tgfbr2 [flox/flox]; p48 [Cre/+]). Representative images of paraffin sections with high or low Pan-Kla expression are shown. (G) Simple linear regression was used to reveal correlation of p-STAT3, CCL2, ARG1, S100A9, and Pan-Kla (n = 12). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.