Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti-PD-1 response in NSCLC

Bonnie L. Bullock; Abigail K. Kimball; Joanna M. Poczobutt; Alexander J. Neuwelt; Howard Y. Li; Amber M. Johnson; Jeff W. Kwak; Emily K. Kleczko; Rachael E. Kaspar; Emily K. Wagner; Katharina Hopp; Erin L. Schenk; Mary C.M. Weiser-Evans; Eric T. Clambey; Raphael A. Nemenoff

doi:10.26508/lsa.201900328

Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti-PD-1 response in NSCLC

Bonnie L. Bullock
, Abigail K. Kimball
, Joanna M. Poczobutt
, Alexander J. Neuwelt
, Howard Y. Li
, Amber M. Johnson
, Jeff W. Kwak
, Emily K. Kleczko
, Rachael E. Kaspar
, Emily K. Wagner
, Katharina Hopp
, Erin L. Schenk
, Mary C.M. Weiser-Evans
, Eric T. Clambey
, Raphael A. Nemenoff

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

Abstract

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.

Original language	English (US)
Article number	e201900328
Journal	Life science alliance
Volume	2
Issue number	3
DOIs	https://doi.org/10.26508/lsa.201900328
State	Published - 2019
Externally published	Yes

Bibliographical note

Funding Information:
We would like to thank Lynn Heasley and Rebecca Tucker for the helpful discussions. This work was supported by the National Institutes of Health (NIH) (R01 CA162226 and CA236222 to RA Nemenoff), Colorado Lung SPORE P50 CA058187 to HY Li and RA Nemenoff, the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service (Career Development Award IK2BX001282 to HY Li), and the NIH/National Center for Advancing Translational Sciences (NCATS) Colorado CTSA TL1 TR001081 to BL Bullock. The University of Colorado Cancer Center Flow Cytometry and the Genomics and Microarray Shared Resources is supported by NIH P30CA046934. The University of Colorado Cancer Center Flow Cytometry Core Facility is funded through a support grant from the National Cancer Institute (P30CA046934). Imaging experiments were performed in the University of Colorado Anschutz Medical Campus Advanced Light Microscopy Core supported in part by NIH/NCATS Colorado Clinical and Translational Sciences Grant Number UL1 TR001082.

Funding Information:
This work was supported by the National Institutes of Health (NIH) (R01 CA162226 and CA236222 to RA Nemenoff), Colorado Lung SPORE P50 CA058187 to HY Li and RA Nemenoff, the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service (Career Development Award IK2BX001282 to HY Li), and the NIH/National Center for Advancing Translational Sciences (NCATS) Colorado CTSA TL1 TR001081 to BL Bullock. The University of Colorado Cancer Center Flow Cytometry and the Genomics and Microarray Shared Resources is supported by NIH P30CA046934. The University of Colorado Cancer Center Flow Cytometry Core Facility is funded through a support grant from the National Cancer Institute (P30CA046934). Imaging experiments were performed in the University of Colorado Anschutz Medical Campus Advanced Light Microscopy Core supported in part by NIH/NCATS Colorado Clinical and Translational Sciences Grant Number UL1 TR001082

Publisher Copyright:
© 2019 Bullock et al.

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SDG 3 Good Health and Well-being

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10.26508/lsa.201900328

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Bullock, B. L., Kimball, A. K., Poczobutt, J. M., Neuwelt, A. J., Li, H. Y., Johnson, A. M., Kwak, J. W., Kleczko, E. K., Kaspar, R. E., Wagner, E. K., Hopp, K., Schenk, E. L., Weiser-Evans, M. C. M., Clambey, E. T., & Nemenoff, R. A. (2019). Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti-PD-1 response in NSCLC. Life science alliance, 2(3), Article e201900328. https://doi.org/10.26508/lsa.201900328

Bullock, BL, Kimball, AK, Poczobutt, JM, Neuwelt, AJ, Li, HY, Johnson, AM, Kwak, JW, Kleczko, EK, Kaspar, RE, Wagner, EK, Hopp, K, Schenk, EL, Weiser-Evans, MCM, Clambey, ET & Nemenoff, RA 2019, 'Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti-PD-1 response in NSCLC', Life science alliance, vol. 2, no. 3, e201900328. https://doi.org/10.26508/lsa.201900328

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title = "Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti-PD-1 response in NSCLC",

abstract = "Targeting PD-1/PD-L1 is only effective in \textasciitilde{}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-L1hi myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFNγ signaling can induce a cascade of changes associated with increased therapeutic vulnerability.",

author = "Bullock, \{Bonnie L.\} and Kimball, \{Abigail K.\} and Poczobutt, \{Joanna M.\} and Neuwelt, \{Alexander J.\} and Li, \{Howard Y.\} and Johnson, \{Amber M.\} and Kwak, \{Jeff W.\} and Kleczko, \{Emily K.\} and Kaspar, \{Rachael E.\} and Wagner, \{Emily K.\} and Katharina Hopp and Schenk, \{Erin L.\} and Weiser-Evans, \{Mary C.M.\} and Clambey, \{Eric T.\} and Nemenoff, \{Raphael A.\}",

note = "Funding Information: We would like to thank Lynn Heasley and Rebecca Tucker for the helpful discussions. This work was supported by the National Institutes of Health (NIH) (R01 CA162226 and CA236222 to RA Nemenoff), Colorado Lung SPORE P50 CA058187 to HY Li and RA Nemenoff, the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service (Career Development Award IK2BX001282 to HY Li), and the NIH/National Center for Advancing Translational Sciences (NCATS) Colorado CTSA TL1 TR001081 to BL Bullock. The University of Colorado Cancer Center Flow Cytometry and the Genomics and Microarray Shared Resources is supported by NIH P30CA046934. The University of Colorado Cancer Center Flow Cytometry Core Facility is funded through a support grant from the National Cancer Institute (P30CA046934). Imaging experiments were performed in the University of Colorado Anschutz Medical Campus Advanced Light Microscopy Core supported in part by NIH/NCATS Colorado Clinical and Translational Sciences Grant Number UL1 TR001082. Funding Information: This work was supported by the National Institutes of Health (NIH) (R01 CA162226 and CA236222 to RA Nemenoff), Colorado Lung SPORE P50 CA058187 to HY Li and RA Nemenoff, the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service (Career Development Award IK2BX001282 to HY Li), and the NIH/National Center for Advancing Translational Sciences (NCATS) Colorado CTSA TL1 TR001081 to BL Bullock. The University of Colorado Cancer Center Flow Cytometry and the Genomics and Microarray Shared Resources is supported by NIH P30CA046934. The University of Colorado Cancer Center Flow Cytometry Core Facility is funded through a support grant from the National Cancer Institute (P30CA046934). Imaging experiments were performed in the University of Colorado Anschutz Medical Campus Advanced Light Microscopy Core supported in part by NIH/NCATS Colorado Clinical and Translational Sciences Grant Number UL1 TR001082 Publisher Copyright: {\textcopyright} 2019 Bullock et al.",

year = "2019",

doi = "10.26508/lsa.201900328",

language = "English (US)",

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T1 - Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti-PD-1 response in NSCLC

AU - Bullock, Bonnie L.

AU - Kimball, Abigail K.

AU - Poczobutt, Joanna M.

AU - Neuwelt, Alexander J.

AU - Li, Howard Y.

AU - Johnson, Amber M.

AU - Kwak, Jeff W.

AU - Kleczko, Emily K.

AU - Kaspar, Rachael E.

AU - Wagner, Emily K.

AU - Hopp, Katharina

AU - Schenk, Erin L.

AU - Weiser-Evans, Mary C.M.

AU - Clambey, Eric T.

AU - Nemenoff, Raphael A.

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PY - 2019

Y1 - 2019

N2 - 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-L1hi myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFNγ signaling can induce a cascade of changes associated with increased therapeutic vulnerability.

AB - 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-L1hi myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFNγ signaling can induce a cascade of changes associated with increased therapeutic vulnerability.

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UR - https://www.scopus.com/pages/publications/85067646922#tab=citedBy

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DO - 10.26508/lsa.201900328

M3 - Article

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AN - SCOPUS:85067646922

SN - 2575-1077

VL - 2

JO - Life science alliance

JF - Life science alliance

IS - 3

M1 - e201900328

ER -

Tumor-intrinsic response to IFNγ shapes the tumor microenvironment and anti-PD-1 response in NSCLC

Abstract

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