Hypoxia-reprogrammed regulatory group 2 innate lymphoid cells promote immunosuppression in pancreatic cancer
Longyun Ye,
Kaizhou Jin,
Zhenyu Liao,
Zhiwen Xiao,
Huaxiang Xu,
Xuan Lin,
Hao Li,
Tianjiao Li,
Wuhu Zhang,
Xuan Han,
Wenquan Wang,
Heli Gao,
Liang Liu,
Weiding Wu,
Xianjun Yu
Affiliations
Longyun Ye
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, 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
Kaizhou Jin
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, 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
Zhenyu Liao
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, 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
Zhiwen Xiao
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, 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
Huaxiang Xu
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, 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
Xuan Lin
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, 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
Hao Li
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, 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
Tianjiao Li
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, 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
Wuhu Zhang
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, 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
Xuan Han
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, 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
Wenquan Wang
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, 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
Heli Gao
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, 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
Liang Liu
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, 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; Corresponding authors at: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, Shanghai 200032, China.
Weiding Wu
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, 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; Corresponding authors at: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, Shanghai 200032, China.
Xianjun Yu
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, 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; Corresponding authors at: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, 270 Dong An Road, Shanghai 200032, China.
Summary: Background: Previously, we uncovered a patient subgroup with highly malignant pancreatic cancer with serum markers CEA+/CA125+/CA19-9 ≥ 1000 U/mL (triple-positive, TP). However, the underlying immunosuppressive mechanism in the tumor immune microenvironment (TIME) of this subgroup is still unknown. Methods: Human tissues were analyzed by flow cytometry, mass cytometry, and immunofluorescence staining. Mouse pancreatic ILC2s were expanded in vivo and used for RNA sequencing, chromatin immunoprecipitation (ChIP), and chemotaxis assays. Findings: Through microarray data, we identified the accumulation of the hypoxia-induced factor-1α (HIF-1α) pathway in these TP patients. Via flow and mass cytometry, we discovered that a special subset of ILC2s were highly infiltrated in TP patients. Under the hypoxia microenvironment, ILC2s were found undergo a transition to a IL10+ regulatory phenotype, we named ILCregs which was correlated with pancreatic ductal adenocarcinoma (PDAC) progression. Further, neoadjuvant chemotherapy could ameliorate hypoxic tumor microenvironments so that significantly reverse the regulatory phenotype of ILCregs. Moreover, most tumor ILC2 were CD103−, which indicated its circulatory origin. The expression of Ccr2 was significantly upregulated on mouse ILCregs, and these cells selectively migrated to CCL2. Interpretation: Our results indicate that the hypoxia microenvironment creates an immunosuppressive TIME by inducing ILCregs from a population of circulating group 2 ILCs in TP PDAC patients. Funding: This study was jointly supported by the National Natural Science Foundation of China (U21A20374, 82173091, and 81701630)
