Targeting neoadjuvant chemotherapy-induced metabolic reprogramming in pancreatic cancer promotes anti-tumor immunity and chemo-response

Rong Tang; Jin Xu; Wei Wang; Qingcai Meng; Chenghao Shao; Yiyin Zhang; Yubin Lei; Zifeng Zhang; Yuan Liu; Qiong Du; Xiangjie Sun; Di Wu; Chen Liang; Jie Hua; Bo Zhang; Xianjun Yu; Si Shi; Chinese Study Group for Pancreatic Cancer

doi:10.1016/j.xcrm.2023.101234

Targeting neoadjuvant chemotherapy-induced metabolic reprogramming in pancreatic cancer promotes anti-tumor immunity and chemo-response

Cell Rep Med. 2023 Oct 17;4(10):101234. doi: 10.1016/j.xcrm.2023.101234.

Authors

Rong Tang¹, Jin Xu¹, Wei Wang², Qingcai Meng¹, Chenghao Shao³, Yiyin Zhang⁴, Yubin Lei⁵, Zifeng Zhang¹, Yuan Liu⁶, Qiong Du⁷, Xiangjie Sun⁸, Di Wu², Chen Liang¹, Jie Hua¹, Bo Zhang¹, Xianjun Yu⁹, Si Shi¹⁰; Chinese Study Group for Pancreatic Cancer

Affiliations

¹ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
² Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
³ Department of Pancreatic-Biliary Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China.
⁴ Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
⁵ Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China.
⁶ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Endoscopy, Fudan University Shanghai Cancer Center, Shanghai, China.
⁷ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.
⁸ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
⁹ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: yuxianjun@fudan.edu.cn.
¹⁰ Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China. Electronic address: shisi@fudanpci.org.

Abstract

The molecular dynamics of pancreatic ductal adenocarcinoma (PDAC) under chemotherapy remain incompletely understood. The widespread use of neoadjuvant chemotherapy (NAC) provides a unique opportunity to investigate PDAC samples post-chemotherapy. Leveraging a cohort from Fudan University Shanghai Cancer Center, encompassing PDAC samples with and without exposure to neoadjuvant albumin-bound paclitaxel and gemcitabine (AG), we have compiled data from single-cell and spatial transcriptomes, proteomes, bulk transcriptomes, and metabolomes, deepening our comprehension of the molecular changes in PDACs in response to chemotherapy. Metabolic flux analysis reveals that NAC induces a reprogramming of PDAC metabolic patterns and enhances immunogenicity. Notably, NAC leads to the downregulation of glycolysis and the upregulation of CD36. Tissue microarray analysis demonstrates that high CD36 expression is linked to poorer survival in patients receiving postoperative AG. Targeting CD36 synergistically improves the PDAC response to AG both in vitro and in vivo, including patient-derived preclinical models.

Keywords: immune microenvironment; neoadjuvant chemotherapy; pancreatic cancer; tumor metabolism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Pancreatic Ductal* / drug therapy
Carcinoma, Pancreatic Ductal* / genetics
China
Deoxycytidine / pharmacology
Humans
Neoadjuvant Therapy
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / genetics
Pancreatic Neoplasms* / metabolism

Substances

Deoxycytidine