Single-cell RNA sequencing to characterize the response of pancreatic cancer to anti-PD-1 immunotherapy

Jing Zhou; Yuexu Jiang; Yue Huang; Qiongling Wang; Jussuf T Kaifi; Eric T Kimchi; Chiswili Yves Chabu; Zhenguo Liu; Trupti Joshi; Guangfu Li

doi:10.1016/j.tranon.2021.101262

Single-cell RNA sequencing to characterize the response of pancreatic cancer to anti-PD-1 immunotherapy

Transl Oncol. 2022 Jan;15(1):101262. doi: 10.1016/j.tranon.2021.101262. Epub 2021 Nov 9.

Authors

Affiliations

¹ Department of Surgery, University of Missouri-Columbia, Medical Sciences Building, M272, Columbia, MO 65212, USA.
² Bond Life Science Center, University of Missouri, Columbia, MO 65212, USA; Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, MO 65212, USA.
³ Department of Surgery, University of Missouri-Columbia, Medical Sciences Building, M272, Columbia, MO 65212, USA; Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO 65212, USA.
⁴ Division of Biological Sciences, University of Missouri, Columbia, MO 65212, USA.
⁵ Center for Precision Medicine and Division of Cardiovascular Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA.
⁶ Bond Life Science Center, University of Missouri, Columbia, MO 65212, USA; Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, MO 65212, USA; Department of Health Management and Informatics, University of Missouri-Columbia, Columbia, MO 65212, USA; MU Institute of Data Science and Informatics, University of Missouri-Columbia, Columbia, MO 65212, USA.
⁷ Department of Surgery, University of Missouri-Columbia, Medical Sciences Building, M272, Columbia, MO 65212, USA; Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO 65212, USA; Department of Molecular Microbiology and Immunology, University of Missouri-Columbia, Columbia, MO 65212, USA. Electronic address: liguan@health.missouri.edu.

Abstract

Pancreatic cancer (PaC) is resistant to immune checkpoint therapy, but the underlying mechanisms are largely unknown. In this study, we have established four orthotopic PaC murine models with different PaC cell lines by intra-pancreatic inoculation. Therapeutic examinations demonstrate that only tumors induced with Panc02-H7 cells respond to αPD-1 antibody treatment, leading to significantly reduced tumor growth and increased survival in the recipient mice. Transcriptomic profiling at a single-cell resolution characterizes the molecular activity of different cells within tumors. Comparative analysis and validated experiments demonstrate that αPD-1-sensitive and -resistant tumors differently shape the immune landscape in the tumor microenvironment (TME) and markedly altering effector CD8⁺ T cells and tumor-associated macrophages (TAMs) in their number, frequency, and gene profile. More exhausted effector CD8⁺ T cells and increased M2-like TAMs with a reduced capacity of antigen presentation are detected in resistant Panc02-formed tumors versus responsive Panc02-H7-formed tumors. Together, our data highlight the correlation of tumor-induced imbalance of macrophages with the fate of tumor-resident effector CD8⁺ T cells and PaC response to αPD-1 immunotherapy. TAMs as a critical regulator of tumor immunity and immunotherapy contribute to PaC resistance to immune checkpoint blockade.

Keywords: Pancreatic cancer (PaC); Programmed cell death protein 1 (PD-1); Single-cell sequencing (scRNA-seq); Tumor-associated macrophages (TAM); αPD-1 antibody (αPD-1 Ab).