Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma

Zoe C. Schmiechen, Ingunn M. Stromnes

Research output: Contribution to journalReview articlepeer-review

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with an overall 5-year survival rate of 10%. Disease lethality is due to late diagnosis, early metastasis and resistance to therapy, including immunotherapy. PDA creates a robust fibroinflammatory tumor microenvironment that contributes to immunotherapy resistance. While previously considered an immune privileged site, evidence demonstrates that in some cases tumor antigen-specific T cells infiltrate and preferentially accumulate in PDA and are central to tumor cell clearance and long-term remission. Nonetheless, PDA can rapidly evade an adaptive immune response using a myriad of mechanisms. Mounting evidence indicates PDA interferes with T cell differentiation into potent cytolytic effector T cells via deficiencies in naive T cell priming, inducing T cell suppression or promoting T cell exhaustion. Mechanistic research indicates that immunotherapy combinations that change the suppressive tumor microenvironment while engaging antigen-specific T cells is required for treatment of advanced disease. This review focuses on recent advances in understanding mechanisms limiting T cell function and current strategies to overcome immunotherapy resistance in PDA.

Original languageEnglish (US)
Article number613815
JournalFrontiers in immunology
Volume11
DOIs
StatePublished - Jan 28 2021

Bibliographical note

Funding Information:
IS is supported by an AACR Pancreatic Cancer Action Network Career Development Award (17-20-25-STRO), AACR Pancreatic Cancer Action Network Catalyst Award (19-35- STRO), an American Cancer Society Institutional Research Grant (124166-IRG-58-001-55-IRG65), and pilot awards from the Masonic Cancer Center and Cancer Research Translational Initiative, (University of Minnesota Medical School) and NIH U54-CA-210190.

Publisher Copyright:
© Copyright © 2021 Schmiechen and Stromnes.

Keywords

  • PD-1
  • PD-L1
  • T cell
  • exhaustion
  • immunosuppression
  • immunotherapy
  • pancreatic cancer
  • pancreatic ductal adenocarcinoma

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

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