Abstract
Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts.
| Original language | English |
|---|---|
| Pages (from-to) | 807-819 |
| Number of pages | 13 |
| Journal | Nature Genetics |
| Volume | 55 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 2023 |
| Externally published | Yes |
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SDG 3 Good Health and Well-being
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In: Nature Genetics, Vol. 55, No. 5, 05.2023, p. 807-819.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer
AU - Ravi, Arvind
AU - Hellmann, Matthew D.
AU - Arniella, Monica B.
AU - Holton, Mark
AU - Freeman, Samuel S.
AU - Naranbhai, Vivek
AU - Stewart, Chip
AU - Leshchiner, Ignaty
AU - Kim, Jaegil
AU - Akiyama, Yo
AU - Griffin, Aaron T.
AU - Vokes, Natalie I.
AU - Sakhi, Mustafa
AU - Kamesan, Vashine
AU - Rizvi, Hira
AU - Ricciuti, Biagio
AU - Forde, Patrick M.
AU - Anagnostou, Valsamo
AU - Riess, Jonathan W.
AU - Gibbons, Don L.
AU - Pennell, Nathan A.
AU - Velcheti, Vamsidhar
AU - Digumarthy, Subba R.
AU - Mino-Kenudson, Mari
AU - Califano, Andrea
AU - Heymach, John V.
AU - Herbst, Roy S.
AU - Brahmer, Julie R.
AU - Schalper, Kurt A.
AU - Velculescu, Victor E.
AU - Henick, Brian S.
AU - Rizvi, Naiyer
AU - Jänne, Pasi A.
AU - Awad, Mark M.
AU - Chow, Andrew
AU - Greenbaum, Benjamin D.
AU - Luksza, Marta
AU - Shaw, Alice T.
AU - Wolchok, Jedd
AU - Hacohen, Nir
AU - Getz, Gad
AU - Gainor, Justin F.
N1 - Funding Information: We express our deep gratitude to the patients and families whose participation enabled this study. We further thank the respective sequencing centers at Yale University, Johns Hopkins University and the Broad Institute of MIT and Harvard for processing the whole exome and RNA-seq data presented here. Funding for this study was provided by a Stand Up To Cancer—American Cancer Society Lung Cancer Dream Team Translational Research Grant (grant SU2C-AACR-DT17-15, Consortium Award). Stand Up to Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of Stand Up To Cancer. This work was additionally supported by The Mark Foundation for Cancer Research (grant 19-029-MIA, Consortium Award) Expanding Therapeutic Options for Lung Cancer (EXTOL) project. Additional funding was provided by a Conquer Cancer Foundation Young Investigator Award (A.R.), an NCI K99 Award for Outstanding Early-Stage Postdoctoral Investigators (A.R.) and Friends of Farber Award (A.R.). A.T.G. was supported, in part, by the Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant 5T32GM007367-43, and in part by the NCI Ruth L. Kirschstein National Research Service Award (NRSA) Individual Fellowship F30CA257765. N.I.V. was supported by an SITC Genentech Fellowship Award, Conquer Cancer YIA and Damon Runyon Mark Foundation Physician-Scientist Training Award. B.R. was supported by a SITC-AstraZeneca Immunotherapy in Lung Cancer Clinical Fellowship Award. P.M.F. was supported by Bloomberg Philanthropies (BKI) and the LUNGevity Lung Cancer Foundation. J.W.R. was supported by a Cancer Center Support Grant (P30CA093373) and a Paul Calabresi Career Development Award for Clinical Oncology (K12CA138464). D.L.G. was supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program (D.L.G. and J.V.H.). M.M. is partially supported by NIH R01 CA240317 (PathoGenetic Analysis of Invasive Mucinous Adenocarcinoma of the Lung). A.C. was supported by the NCI Cancer Target Discovery and Development Program (U01 CA217858), an NCI Outstanding Investigator Award (R35 CA197745) and NIH Shared Instrumentation Grants (S10 OD012351 and S1 0OD021764), as well as in part through the NCI Cancer Center Support Grant (P30 CA013696). B.D.G. was additionally supported in part through the NIH/NCI Cancer Center Support Grant P30 (CA008748); the Pershing Square Sohn Prize-Mark Foundation Fellowship; a collaboration by Stand Up To Cancer, a program of the Entertainment Industry Foundation, the Society for Immunotherapy of Cancer and the Lustgarten Foundation. J.W. was supported in part through the NIH/NCI Cancer Center Support Grant P30 (CA008748), the Ludwig Collaborative and Swim Across America Laboratory, the Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medicine. N.H. is currently David P. Ryan, MD, Chair funded by a gift from Arther, Sandra and Sarah Irving, and is additionally supported by NIH/NCI (RO1CA208756). M.D.H. is a Damon Runyon Clinical Investigator supported in part by the Damon Runyon Cancer Research Foundation (CI-98-18). A.C. was supported by a Clinical Investigator Award from National Cancer Institute (K08 CA-248723). Funding Information: We express our deep gratitude to the patients and families whose participation enabled this study. We further thank the respective sequencing centers at Yale University, Johns Hopkins University and the Broad Institute of MIT and Harvard for processing the whole exome and RNA-seq data presented here. Funding for this study was provided by a Stand Up To Cancer—American Cancer Society Lung Cancer Dream Team Translational Research Grant (grant SU2C-AACR-DT17-15, Consortium Award). Stand Up to Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of Stand Up To Cancer. This work was additionally supported by The Mark Foundation for Cancer Research (grant 19-029-MIA, Consortium Award) Expanding Therapeutic Options for Lung Cancer (EXTOL) project. Additional funding was provided by a Conquer Cancer Foundation Young Investigator Award (A.R.), an NCI K99 Award for Outstanding Early-Stage Postdoctoral Investigators (A.R.) and Friends of Farber Award (A.R.). A.T.G. was supported, in part, by the Ruth L. Kirschstein National Research Service Award (NRSA) Institutional Research Training Grant 5T32GM007367-43, and in part by the NCI Ruth L. Kirschstein National Research Service Award (NRSA) Individual Fellowship F30CA257765. N.I.V. was supported by an SITC Genentech Fellowship Award, Conquer Cancer YIA and Damon Runyon Mark Foundation Physician-Scientist Training Award. B.R. was supported by a SITC-AstraZeneca Immunotherapy in Lung Cancer Clinical Fellowship Award. P.M.F. was supported by Bloomberg Philanthropies (BKI) and the LUNGevity Lung Cancer Foundation. J.W.R. was supported by a Cancer Center Support Grant (P30CA093373) and a Paul Calabresi Career Development Award for Clinical Oncology (K12CA138464). D.L.G. was supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program (D.L.G. and J.V.H.). M.M. is partially supported by NIH R01 CA240317 (PathoGenetic Analysis of Invasive Mucinous Adenocarcinoma of the Lung). A.C. was supported by the NCI Cancer Target Discovery and Development Program (U01 CA217858), an NCI Outstanding Investigator Award (R35 CA197745) and NIH Shared Instrumentation Grants (S10 OD012351 and S1 0OD021764), as well as in part through the NCI Cancer Center Support Grant (P30 CA013696). B.D.G. was additionally supported in part through the NIH/NCI Cancer Center Support Grant P30 (CA008748); the Pershing Square Sohn Prize-Mark Foundation Fellowship; a collaboration by Stand Up To Cancer, a program of the Entertainment Industry Foundation, the Society for Immunotherapy of Cancer and the Lustgarten Foundation. J.W. was supported in part through the NIH/NCI Cancer Center Support Grant P30 (CA008748), the Ludwig Collaborative and Swim Across America Laboratory, the Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, and Weill Cornell Medicine. N.H. is currently David P. Ryan, MD, Chair funded by a gift from Arther, Sandra and Sarah Irving, and is additionally supported by NIH/NCI (RO1CA208756). M.D.H. is a Damon Runyon Clinical Investigator supported in part by the Damon Runyon Cancer Research Foundation (CI-98-18). A.C. was supported by a Clinical Investigator Award from National Cancer Institute (K08 CA-248723). Publisher Copyright: © 2023, The Author(s).
PY - 2023/5
Y1 - 2023/5
N2 - Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts.
AB - Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts.
UR - https://www.scopus.com/pages/publications/85152082421
U2 - 10.1038/s41588-023-01355-5
DO - 10.1038/s41588-023-01355-5
M3 - Article
C2 - 37024582
AN - SCOPUS:85152082421
SN - 1061-4036
VL - 55
SP - 807
EP - 819
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -