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Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti–PD-1 response in NSCLC
Targeting PD-1/PD-L1 is only effective in ∼20% of lung cancer patients, but determinants of this response are poorly defined. We previously observed differential responses of two murine K-Ras–mutant lung cancer cell lines to anti–PD-1 therapy: CMT167 tumors were eliminated, whereas Lewis Lung Carcin...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Life Science Alliance LLC
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537751/ https://www.ncbi.nlm.nih.gov/pubmed/31133614 http://dx.doi.org/10.26508/lsa.201900328 |
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author | Bullock, Bonnie L Kimball, Abigail K Poczobutt, Joanna M Neuwelt, Alexander J Li, Howard Y Johnson, Amber M Kwak, Jeff W Kleczko, Emily K Kaspar, Rachael E Wagner, Emily K Hopp, Katharina Schenk, Erin L Weiser-Evans, Mary CM Clambey, Eric T Nemenoff, Raphael A |
author_facet | Bullock, Bonnie L Kimball, Abigail K Poczobutt, Joanna M Neuwelt, Alexander J Li, Howard Y Johnson, Amber M Kwak, Jeff W Kleczko, Emily K Kaspar, Rachael E Wagner, Emily K Hopp, Katharina Schenk, Erin L Weiser-Evans, Mary CM Clambey, Eric T Nemenoff, Raphael A |
author_sort | Bullock, Bonnie L |
collection | PubMed |
description | Targeting PD-1/PD-L1 is only effective in ∼20% of lung cancer patients, but determinants of this response are poorly defined. We previously observed differential responses of two murine K-Ras–mutant lung cancer cell lines to anti–PD-1 therapy: CMT167 tumors were eliminated, whereas Lewis Lung Carcinoma (LLC) tumors were resistant. The goal of this study was to define mechanism(s) mediating this difference. RNA sequencing analysis of cancer cells recovered from lung tumors revealed that CMT167 cells induced an IFNγ signature that was blunted in LLC cells. Silencing Ifngr1 in CMT167 resulted in tumors resistant to IFNγ and anti–PD-1 therapy. Conversely, LLC cells had high basal expression of SOCS1, an inhibitor of IFNγ. Silencing Socs1 increased response to IFNγ in vitro and sensitized tumors to anti–PD-1. This was associated with a reshaped tumor microenvironment, characterized by enhanced T cell infiltration and enrichment of PD-L1(hi) myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFNγ signaling can induce a cascade of changes associated with increased therapeutic vulnerability. |
format | Online Article Text |
id | pubmed-6537751 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Life Science Alliance LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-65377512019-06-06 Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti–PD-1 response in NSCLC Bullock, Bonnie L Kimball, Abigail K Poczobutt, Joanna M Neuwelt, Alexander J Li, Howard Y Johnson, Amber M Kwak, Jeff W Kleczko, Emily K Kaspar, Rachael E Wagner, Emily K Hopp, Katharina Schenk, Erin L Weiser-Evans, Mary CM Clambey, Eric T Nemenoff, Raphael A Life Sci Alliance Research Articles Targeting PD-1/PD-L1 is only effective in ∼20% of lung cancer patients, but determinants of this response are poorly defined. We previously observed differential responses of two murine K-Ras–mutant lung cancer cell lines to anti–PD-1 therapy: CMT167 tumors were eliminated, whereas Lewis Lung Carcinoma (LLC) tumors were resistant. The goal of this study was to define mechanism(s) mediating this difference. RNA sequencing analysis of cancer cells recovered from lung tumors revealed that CMT167 cells induced an IFNγ signature that was blunted in LLC cells. Silencing Ifngr1 in CMT167 resulted in tumors resistant to IFNγ and anti–PD-1 therapy. Conversely, LLC cells had high basal expression of SOCS1, an inhibitor of IFNγ. Silencing Socs1 increased response to IFNγ in vitro and sensitized tumors to anti–PD-1. This was associated with a reshaped tumor microenvironment, characterized by enhanced T cell infiltration and enrichment of PD-L1(hi) myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFNγ signaling can induce a cascade of changes associated with increased therapeutic vulnerability. Life Science Alliance LLC 2019-05-27 /pmc/articles/PMC6537751/ /pubmed/31133614 http://dx.doi.org/10.26508/lsa.201900328 Text en © 2019 Bullock et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Articles Bullock, Bonnie L Kimball, Abigail K Poczobutt, Joanna M Neuwelt, Alexander J Li, Howard Y Johnson, Amber M Kwak, Jeff W Kleczko, Emily K Kaspar, Rachael E Wagner, Emily K Hopp, Katharina Schenk, Erin L Weiser-Evans, Mary CM Clambey, Eric T Nemenoff, Raphael A Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti–PD-1 response in NSCLC |
title | Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti–PD-1 response in NSCLC |
title_full | Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti–PD-1 response in NSCLC |
title_fullStr | Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti–PD-1 response in NSCLC |
title_full_unstemmed | Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti–PD-1 response in NSCLC |
title_short | Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti–PD-1 response in NSCLC |
title_sort | tumor-intrinsic response to ifnγ shapes the tumor microenvironment and anti–pd-1 response in nsclc |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537751/ https://www.ncbi.nlm.nih.gov/pubmed/31133614 http://dx.doi.org/10.26508/lsa.201900328 |
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