ZEB1 promotes chemoimmunotherapy resistance in pancreatic cancer models by downregulating chromatin acetylation of CXCL16
Shaobo Zhang, Yumeng Hu, Zhijun Zhou, Gaoyuan Lv, Chenze Zhang, Yuanyuan Guo, Fangxia Wang, Yuxin Ye, Haoran Qi, Hui Zhang, Wenming Wu, Min Li, Mingyang Liu
Shaobo Zhang, Yumeng Hu, Zhijun Zhou, Gaoyuan Lv, Chenze Zhang, Yuanyuan Guo, Fangxia Wang, Yuxin Ye, Haoran Qi, Hui Zhang, Wenming Wu, Min Li, Mingyang Liu
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Research Article Cell biology Oncology

ZEB1 promotes chemoimmunotherapy resistance in pancreatic cancer models by downregulating chromatin acetylation of CXCL16

Abstract

Pancreatic cancer (PC) is notoriously resistant to both chemotherapy and immunotherapy, presenting a major therapeutic challenge. Epigenetic modifications play a critical role in PC progression, yet their contribution to chemoimmunotherapy resistance remains poorly understood. Here, we identified the transcription factor ZEB1 as a critical driver of chemoimmunotherapy resistance in PC. ZEB1 knockdown synergized with gemcitabine and anti–PD-1 therapy, markedly suppressed PC growth, and prolonged survival in vivo. Single-cell and spatial transcriptomics revealed that ZEB1 ablation promoted tumor pyroptosis by recruiting and activating GZMA+CD8+ T cells in the tumor core through epigenetic upregulation of CXCL16. Meanwhile, ZEB1 blockade attenuates CD44+ neutrophil–induced CD8+ T cell exhaustion by reducing tumor-derived SPP1 secretion, which otherwise promotes exhaustion through activation of the PD-L1/PD-1 pathway. Clinically, high ZEB1 expression correlated with chemoresistance, immunosuppression, and diminished CXCL16 levels in patients with PC. Importantly, the epigenetic inhibitor mocetinostat (targeting ZEB1) potentiated the efficacy of chemoimmunotherapy, including anti–PD-1 and CAR T therapies, in patient-derived organoids, xenografts, and orthotopic models. Our study unveils ZEB1 as a master epigenetic regulator of chemoimmunotherapy resistance and proposes its targeting as a transformative strategy for PC treatment.

Authors

Shaobo Zhang, Yumeng Hu, Zhijun Zhou, Gaoyuan Lv, Chenze Zhang, Yuanyuan Guo, Fangxia Wang, Yuxin Ye, Haoran Qi, Hui Zhang, Wenming Wu, Min Li, Mingyang Liu

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Figure 4

Zeb1 promotes recruitment of neutrophil and drives their polarization toward an immunosuppressive phenotype.

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Zeb1 promotes recruitment of neutrophil and drives their polarization to...
(A) Circle plots compare the strengths of cell-cell interactions between granulocytes and other cell types. (B) Neutrophil migration assay. Relative migration of mouse neutrophils after coculture with KPC-shV and -shZeb1 cells for 12 hours. (C) Violin plot showing AUCell scores of the N1 and N2 gene sets in neutrophils derived from the shV and shZeb1 models. (D) Neutrophil activation. Detection of N1 polarization markers (Icam, Cxcl10, Tnfa) and the N2 polarization marker Cxcr2 in neutrophils by qPCR after coculturing with KPC-shV or -shZeb1 cells for 12 hours. (E) Relative migration of mouse CD8+ T cells after coculturing with neutrophils. (F) Schematic of a 3-cell coculture system. (G) CD8+ T cells were isolated from the 3-cell coculture systems, and levels of activation markers were detected by qPCR. (H) Neutrophils were isolated from the 3-cell cocultured system, and levels of N1 and N2 polarization markers were detected by qPCR. (I and J) Tumor images and weight of orthotopic allograft mouse model established from KPC-shV and -shZeb1 cells and treated with gemcitabine (50 mg/kg) and anti-Ly6g (25 μg) 3 times a week (n = 5). Data are representative of at least 3 (B, D, E, G, and H) independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, by unpaired, 2-tailed Student’s t test (B, D, E, G, and H), Wilcoxon’s rank-sum test (C), and 1-way ANOVA with Tukey’s multiple-comparison test (J). Data are presented as mean ± SD in B, D, E, G, H, and J.