Intra-tumoral infiltration of adipocyte facilitates the activation of antitumor immune response in pancreatic ductal adenocarcinoma

Xiaomeng Liu; Jiang Liu; Jin Xu; Bo Zhang; Miaoyan Wei; Jialin Li; Hang Xu; Xianjun Yu; Wei Wang; Si Shi

doi:10.1016/j.tranon.2022.101561

Intra-tumoral infiltration of adipocyte facilitates the activation of antitumor immune response in pancreatic ductal adenocarcinoma

Transl Oncol. 2023 Jan:27:101561. doi: 10.1016/j.tranon.2022.101561. Epub 2022 Oct 17.

Authors

Xiaomeng Liu¹, Jiang Liu¹, Jin Xu¹, Bo Zhang¹, Miaoyan Wei¹, Jialin Li¹, Hang Xu¹, Xianjun Yu¹, Wei Wang², Si Shi³

Affiliations

¹ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
² Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. Electronic address: wangwei@fudanpci.org.
³ Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China. Electronic address: shisi@fudanpci.org.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy that is characterized by an immunosuppressive microenvironment. The immune suppression in PDAC is largely driven by heterogeneous stromal and tumor cells. However, how adipocyte in the tumor microenvironment (TME) is related to the immune cell infiltration in PDAC has rarely been published. We identified adipocytes by performing bioinformatics analyses, and explored the clinical outcomes and TME characters in PDAC with different levels of adipocyte infiltration. Interestingly, in contrast to adiposity, high adipocyte infiltration in the TME was related to significantly increased median overall survival and a lower total tumor mutational burden. Functionally, high adipocyte infiltration was associated with the immune response, particularly with the abundant cytokine infiltration in PDAC samples. Moreover, adipocyte infiltration in the TME was positively associated with anticancer signatures in the immune microenvironment. Immunohistochemistry and RT-PCR were performed with PDAC tissue samples from our center to study the expression of adipocytes in PDAC. The mature adipocytes were strongly associated with the immune composition and prognosis of patients with PDAC. Primary adipocytes were isolated from mice to construct a PDAC transplantation tumor model. In vivo experiments showed that adipocytes elicited increased CD8+ T cell infiltration and potent antitumor activity in tumor-bearing mice. Overall, we innovatively found that adipocytes facilitated the antitumor immune response in the TME by performing mouse experiments and analyzing PDAC samples. This study provides a new perspective on the activation of the immune microenvironment in PDAC.

Keywords: Adipocyte infiltration; Antitumor immune response; Cytokine infiltration; Pancreatic cancer; Tumor microenvironment.