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Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma

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 t...

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Autores principales: Schmiechen, Zoe C., Stromnes, Ingunn M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876239/
https://www.ncbi.nlm.nih.gov/pubmed/33584701
http://dx.doi.org/10.3389/fimmu.2020.613815
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author Schmiechen, Zoe C.
Stromnes, Ingunn M.
author_facet Schmiechen, Zoe C.
Stromnes, Ingunn M.
author_sort Schmiechen, Zoe C.
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description 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.
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spelling pubmed-78762392021-02-12 Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma Schmiechen, Zoe C. Stromnes, Ingunn M. Front Immunol Immunology 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. Frontiers Media S.A. 2021-01-28 /pmc/articles/PMC7876239/ /pubmed/33584701 http://dx.doi.org/10.3389/fimmu.2020.613815 Text en Copyright © 2021 Schmiechen and Stromnes http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Schmiechen, Zoe C.
Stromnes, Ingunn M.
Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma
title Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma
title_full Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma
title_fullStr Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma
title_full_unstemmed Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma
title_short Mechanisms Governing Immunotherapy Resistance in Pancreatic Ductal Adenocarcinoma
title_sort mechanisms governing immunotherapy resistance in pancreatic ductal adenocarcinoma
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876239/
https://www.ncbi.nlm.nih.gov/pubmed/33584701
http://dx.doi.org/10.3389/fimmu.2020.613815
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