Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma
Kang Sun, … , Xueli Bai, Tingbo Liang
Kang Sun, … , Xueli Bai, Tingbo Liang
Published January 30, 2025
Citation Information: J Clin Invest. 2025;135(7):e187024. https://doi.org/10.1172/JCI187024.
View: Text | PDF
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

×

Figure 2

Elevated lactylation is associated with immunotherapy resistance in PDAC.

Options: View larger image (or click on image) Download as PowerPoint
Elevated lactylation is associated with immunotherapy resistance in PDAC...
(A) Kaplan-Meier survival curves of PFS for patients with PDAC based on the impact of 18F-FDG uptake with treatment. The median of 18F-FDG SUVmax was used to divide the cohort (cut off: 8.1). Statistical analyses were performed with log-rank test. (B) Representative images of 18F-FDG PET/CT and computed tomography angiography (CTA) of patients. Tumors are shown with a blue arrow. (C) Pan-Kla levels were analyzed by immunostaining of 31 biopsy specimens. Representative images of patients are shown. Scale bars: 2 cm. (D) Overall survival analysis was performed based on mean fluorescence intensity of Pan-Kla immunostaining. (E) ROC-AUC plot analysis was performed based on mean fluorescence intensity of Pan-Kla. Statistical analyses were performed with log-rank test. Prediction model of immunochemotherapy response situation was established. (F) Glycolysis score of patients with different KRAS mutation status using TCGA-PAAD database. Statistical analyses were performed with 1-way ANOVA. (G) Protein expression analysis of KPC cells treated with MRTX1133 (1 μM, 24 hours) or DMSO. (H) Representative images of 18FDG PET/CT of KPC orthotopic transplantation model treated with MRTX1133 (0.2 mg/mouse, i.p., qd) or DMSO. Tumors are shown with a white arrow. (I) Orthotopic transplantation tumors and statistical analysis are shown. KPC mice were individually treated by anti–PD-1 mAb (100 μg/mouse, i.p., tid) or MRTX1133 (0.2 mg/mouse, i.p., qd). Statistical analyses were performed with 1-way ANOVA (n = 5). (J) Proportions of each type of immunocytes and function markers in CD8+ T cells. The immune microenvironments of orthotopic transplantation model with different treatments were compared. Statistical analyses were performed with 1-way ANOVA (n = 5). *P < 0.05; **P < 0.01; ***P < 0.001.