Stratified analysis identifies HIF-2 α as a therapeutic target for highly immune-infiltrated melanomas.

Autor:	Huang AY; Dana-Farber Cancer Institute, Boston, MA, USA.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Massachusetts Institute of Technology, Cambridge, USA., Burke KP; Dana-Farber Cancer Institute, Boston, MA, USA.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Porter R; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Meiger L; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Fatouros P; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Yang J; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Massachusetts Institute of Technology, Cambridge, USA.; Rutgers University, New Brunswick, NJ, USA., Robitschek E; Dana-Farber Cancer Institute, Boston, MA, USA.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA., Vokes N; University of Texas MD Anderson Cancer Center, Houston, USA., Ricker C; Dana-Farber Cancer Institute, Boston, MA, USA.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA., Rosado V; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Tarantino G; Dana-Farber Cancer Institute, Boston, MA, USA.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Harvard Medical School, Boston, MA, USA., Chen J; Dana-Farber Cancer Institute, Boston, MA, USA.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA., Aprati TJ; Dana-Farber Cancer Institute, Boston, MA, USA.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA., Glettig MC; Dana-Farber Cancer Institute, Boston, MA, USA.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; ETH Zürich, Zurich, Switzerland., He Y; Dana-Farber Cancer Institute, Boston, MA, USA.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA., Wang C; Massachusetts Institute of Technology, Cambridge, USA., Fu D; Massachusetts Institute of Technology, Cambridge, USA., Ho LL; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Massachusetts Institute of Technology, Cambridge, USA., Galani K; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Massachusetts Institute of Technology, Cambridge, USA., Freeman GJ; Dana-Farber Cancer Institute, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Buchbinder EI; Dana-Farber Cancer Institute, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Stephen Hodi F; Dana-Farber Cancer Institute, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Kellis M; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Massachusetts Institute of Technology, Cambridge, USA., Boland GM; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Harvard Medical School, Boston, MA, USA.; Massachusetts General Hospital, Boston, MA, USA., Sharpe AH; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Liu D; Dana-Farber Cancer Institute, Boston, MA, USA.; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.; Harvard Medical School, Boston, MA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 30. Date of Electronic Publication: 2024 Oct 30.
DOI:	10.1101/2024.10.29.620300
Abstrakt:	While immune-checkpoint blockade (ICB) has revolutionized treatment of metastatic melanoma over the last decade, the identification of broadly applicable robust biomarkers has been challenging, driven in large part by the heterogeneity of ICB regimens and patient and tumor characteristics. To disentangle these features, we performed a standardized meta-analysis of eight cohorts of patients treated with anti-PD-1 (n=290), anti-CTLA-4 (n=175), and combination anti-PD-1/anti-CTLA-4 (n=51) with RNA sequencing of pre-treatment tumor and clinical annotations. Stratifying by immune-high vs -low tumors, we found that surprisingly, high immune infiltrate was a biomarker for response to combination ICB, but not anti-PD-1 alone. Additionally, hypoxia-related signatures were associated with non-response to anti-PD-1, but only amongst immune infiltrate-high melanomas. In a cohort of scRNA-seq of patients with metastatic melanoma, hypoxia also correlated with immunosuppression and changes in tumor-stromal communication in the tumor microenvironment (TME). Clinically actionable targets of hypoxia signaling were also uniquely expressed across different cell types. We focused on one such target, HIF-2 α , which was specifically upregulated in endothelial cells and fibroblasts but not in immune cells or tumor cells. HIF-2 α inhibition, in combination with anti-PD-1, enhanced tumor growth control in pre-clinical models, but only in a more immune-infiltrated melanoma model. Our work demonstrates how careful stratification by clinical and molecular characteristics can be leveraged to derive meaningful biological insights and lead to the rational discovery of novel clinical targets for combination therapy. Competing Interests: Conflict of interest/Competing interest A.H.S. has patents/pending royalties on the PD-1 pathway from Roche and Novartis and has research funding from AbbVie, TaiwanBio, and Calico unrelated to the submitted work. A.H.S. serves on advisory boards for Elpiscience, Monopteros, Alixia, Corner Therapeutics, Bioentre, Amgen, Glaxo Smith Kline, and Janssen. She also is on scientific advisory boards for the Massachusetts General Cancer Center, Program in Cellular and Molecular Medicine at Boston Children’s Hospital, the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center, Perlmutter Cancer Center at NYU, the Gladstone Institutes, and the John Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy. She is an academic editor for the Journal of Experimental Medicine. G.J.F. has patents/royalties on the PD-L1/PD-1 pathway from Roche, Merck MSD, Bristol-Myers-Squibb, Merck KGA, Boehringer-Ingelheim, AstraZeneca, Dako, Leica, Mayo Clinic, Eli Lilly, and Novartis. G.J.F. has served on advisory boards for iTeos, NextPoint, IgM, GV20, IOME, Bioentre, Santa Ana Bio, Simcere of America, and Geode. G.J.F. has equity in Nextpoint, iTeos, IgM, Invaria, GV20, Bioentre, and Geode. G.M.B. discloses the following financial and professional collaborations: Takeda Oncology – sponsored research agreement, Olink Proteomics – sponsored research agreement, Novartis – scientific advisory board, speaker, Nektar Therapeutics – scientific advisory board, steering committee, Palleon Pharmaceuticals – sponsored research agreement, InterVenn Biosciences – sponsored research agreement, scientific advisory board, Merck – scientific advisory board, consulting, Iovance - scientific advisory board, Ankyra Therapeutics – scientific advisory board, equity. F.S.H. reports grants and personal fees from Bristol-Myers Squibb, personal fees from Merck, grants and personal fees from Novartis, personal fees from Compass Therapeutics, personal fees from Apricity, personal fees from 7 Hills Pharma, personal fees from Bicara, personal fees from Checkpoint Therapeutics, personal fees from Genentech/Roche, personal fees from Bioentre, personal fees from Gossamer, personal fees from Iovance, personal fees from Catalym, personal fees from Immunocore, personal fees from Kairos, personal fees from Rheos, personal fees from Bayer, personal fees from Zumutor, personal fees from Corner Therapeuitcs, personal fees from Puretech, personal fees from Curis, personal fees from Astra Zeneca, personal fees from Pliant, personal fees from Solu Therapeutics, personal fees from Vir Biotechnology, personal fees from 92Bio, outside the submitted work; In addition, F.S.H. has a patent “Methods for Treating MICA-Related Disorders” (#20100111973) with royalties paid, a patent “Tumor antigens and uses thereof” (#7250291) issued, a patent “Angiopoieten-2 Biomarkers Predictive of Anti-immune checkpoint response” (#20170248603) pending, a patent “Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms” (#20160340407) pending, a patent “Therapeutic peptides ”(#20160046716) pending, a patent “Therapeutic Peptides” (#20140004112) pending, a patent “Therapeutic Peptides” (#20170022275) pending, a patent “Therapeutic Peptides” (#20170008962) pending, a patent “Therapeutic Peptides” (#9402905) issued, a patent “METHODS OF USING PEMBROLIZUMAB AND TREBANANIB” pending, a patent “Vaccine compositions and methods for restoring NKG2D pathway function against cancers” (#10279021) with royalties paid, a patent “antibodies that bind to MHC Class I polypeptide-related sequence”, a patent (#10106611) issued, a patent “ANTI-GALECTIN ANTIBODY BIOMARKERS PREDICTIVE OF ANTI-IMMUNE CHECKPOINT AND ANTI-ANGIOGENESIS RESPONSES” (publication number #20170343552) pending, and a patent “Antibodies against EDIL3 and methods of use thereof” pending. D.L. reports receiving personal fees from Genentech, and served on the Scientific Advisory Board for Oncovalent Therapeutics, outside the current work.
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