Culprits of PDAC resistance to gemcitabine and immune checkpoint inhibitor: Tumour microenvironment components

Sheng-Kai Hsu; Mahendra Jadhao; Wei-Ting Liao; Wen-Tsan Chang; Chun-Tzu Hung; Chien-Chih Chiu

doi:10.3389/fmolb.2022.1020888

Culprits of PDAC resistance to gemcitabine and immune checkpoint inhibitor: Tumour microenvironment components

Front Mol Biosci. 2022 Oct 10:9:1020888. doi: 10.3389/fmolb.2022.1020888. eCollection 2022.

Authors

Sheng-Kai Hsu^{1

2}, Mahendra Jadhao^{3

4}, Wei-Ting Liao¹, Wen-Tsan Chang^{5

6

7}, Chun-Tzu Hung¹, Chien-Chih Chiu^{1

7

8

9

10}

Affiliations

¹ Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
² Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
³ Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁴ Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
⁵ Division of General and Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
⁶ Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁷ Center for Cancer Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
⁸ Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
⁹ Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
¹⁰ National Laboratory Animal Center, National Applied Research Laboratories, Taipei, Taiwan.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer with a dismal five-year survival rate of 11%. Despite remarkable advancements in cancer therapeutics, PDAC patients rarely benefit from it due to insurmountable treatment resistance. Notably, PDAC is pathologically characterized by an extensive desmoplastic reaction and an extremely immunosuppressive tumour microenvironment (TME). The PDAC TME consists of cell components (e.g., tumour, immune and stromal cells) and noncellular components (e.g., extracellular matrix), exhibiting high complexity and their interplay resulting in resistance to chemotherapeutics and immune checkpoint inhibitors. In our review, we shed light on how crosstalk of complex environmental components modulates PDAC drug resistance, and we summarize related clinical trials. Moreover, we extend our discussion on TME exploration and exosome analysis, providing new insights into clinical applications, including personalized medicine, disease monitoring and drug carriers.

Keywords: ICI resistance; chemoresistance; desmoplasia; immunomodulation; pancreatic ductal adenocarcinoma; tumour microenvironment.

Publication types

Review