학술논문
Germline immunomodulatory expression quantitative trait loci (ieQTLs) associated with immune-related toxicity from checkpoint inhibition.
Document Type
Academic Journal
Author
Ferguson R; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Departments of Population Health and Environmental Medicine, New York University-Grossman School of Medicine, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA.; Chat V; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Departments of Population Health and Environmental Medicine, New York University-Grossman School of Medicine, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA.; Morales L; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Departments of Population Health and Environmental Medicine, New York University-Grossman School of Medicine, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA.; Simpson D; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Departments of Population Health and Environmental Medicine, New York University-Grossman School of Medicine, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA.; Monson KR; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Departments of Population Health and Environmental Medicine, New York University-Grossman School of Medicine, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA.; Cohen E; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Departments of Population Health and Environmental Medicine, New York University-Grossman School of Medicine, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA.; Zusin S; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Departments of Population Health and Environmental Medicine, New York University-Grossman School of Medicine, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA.; Madonna G; Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy.; Capone M; Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy.; Simeone E; Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy.; Pavlick A; Division of Hematology & Medical Oncology, the Cutaneous Oncology Program, Weill Cornell Medicine and New York-Presbyterian, New York, USA.; Luke JJ; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA; UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA.; Gajewski TF; Department of Pathology, University of Chicago, Chicago, IL, USA; Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA; Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.; Osman I; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA; Department of Medicine, New York University-Grossman School of Medicine, New York, NY, USA; Ronald O. Perelman Department of Dermatology, New York University-Grossman School of Medicine, New York, NY, USA.; Ascierto P; Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy.; Weber J; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA; Department of Medicine, New York University-Grossman School of Medicine, New York, NY, USA.; Kirchhoff T; Laura and Isaac Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA; Departments of Population Health and Environmental Medicine, New York University-Grossman School of Medicine, New York, NY, USA; The Interdisciplinary Melanoma Cooperative Group, New York University-Grossman School of Medicine, New York, NY, USA. Electronic address: Tomas.Kirchhoff@nyulangone.org.
Source
Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 9005373 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0852 (Electronic) Linking ISSN: 09598049 NLM ISO Abbreviation: Eur J Cancer Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Immune checkpoint inhibition (ICI) has improved clinical outcomes for metastatic melanoma patients; however, 65-80% of patients treated with ICI experience immune-related adverse events (irAEs). Given the plausible link of irAEs with underlying host immunity, we explored whether germline genetic variants controlling the expression of 42 immunomodulatory genes were associated with the risk of irAEs in melanoma patients treated with the single-agent anti-CTLA-4 antibody ipilimumab (IPI).
Methods: We identified 42 immunomodulatory expression quantitative trait loci (ieQTLs) most significantly associated with the expression of 382 immune-related genes. These germline variants were genotyped in IPI-treated melanoma patients, collected as part of a multi-institutional collaboration. We tested the association of ieQTLs with irAEs in a discovery cohort of 95 patients, followed by validation in an additional 97 patients.
Results: We found that the alternate allele of rs7036417, a variant linked to increased expression of SYK, was strongly associated with an increased risk of grade 3-4 toxicity [odds ratio (OR) = 7.46; 95% confidence interval (CI) = 2.65-21.03; p = 1.43E-04]. This variant was not associated with response (OR = 0.90; 95% CI = 0.37-2.21; p = 0.82).
Conclusion: We report that rs7036417 is associated with increased risk of severe irAEs, independent of IPI efficacy. SYK plays an important role in B-cell/T-cell expansion, and increased pSYK has been reported in patients with autoimmune disease. The association between rs7036417 and IPI irAEs in our data suggests a role of SYK overexpression in irAE development. These findings support the hypothesis that inherited variation in immune-related pathways modulates ICI toxicity and suggests SYK as a possible future target for therapies to reduce irAEs.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RF, VC, LM, DS, KM, EC, SZ, GM, MC, ES, IO and TK have no competing interests to report. AP: consultant for BMS, Merck and Regeneron. JL is on Data and Safety Monitoring Board (DSMB): Abbvie, Agenus, Amgen, Immutep and Evaxion; Scientific Advisory Board: (no stock) 7 Hills, Affivant, BioCytics, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio (stock) Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, physIQ, Pyxis, Saros, STipe and Tempest; consultancy with compensation: Abbvie, Agenus, Alnylam, Atomwise, Bayer, Bristol-Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Replimmune, Ribon, Roivant, Servier, STINGthera, Synlogic and Synthekine; research support: (all to institution for clinical trials unless noted) AbbVie, Astellas, Astrazeneca, Bristol-Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona and Xencor; patents: (both provisional) Serial #15/612657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). TFG is a consultant on advisory boards for Merck, Jounce, Fog Pharma, Adaptimmune, Pyxis, Allogene, Catalym, Bicara, Maia and Samyang; he has research support from BMS, Merck, Seattle Genetics, Evelo, Bayer and Pyxis; he has intellectual property/licensing with Aduro, Evelo and BMS and is a co-founder/shareholder for Jounce and Pyxis. PAA has/had consultant/advisory roles for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna and Bio-Al Health. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer and Sanofi; all of the above took place outside the submitted work. JW owns stock or other ownership at Altor BioScience, Biond, CytomX Therapeutics; received honoraria from Bristol-Myers Squibb, Merck, Genentech, AbbVie, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Eisai, Altor BioScience, Amgen, Roche, Ichor Medical Systems, Celldex, CytomX Therapeutics, Nektar, Novartis, Sellas, WindMIL and Takeda; has consulting/advisory role at Celldex, Ichor Medical Systems, Biond, Altor BioScience, Bristol-Myers Squibb, Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, AbbVie, Eisai, CytomX Therapeutics, Nektar, Novartis, Sellas, WindMIL and Takeda; obtained research funding (to the institution) from Bristol-Myers Squibb, Merck, GlaxoSmithKline, Genentech, Astellas Pharma, Incyte, Roche and Novartis; and received funding for travel/accommodations/expenses from Bristol-Myers Squibb, GlaxoSmithKline, Daiichi Sankyo, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech, Novartis, WindMIL and Takeda.
(Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Methods: We identified 42 immunomodulatory expression quantitative trait loci (ieQTLs) most significantly associated with the expression of 382 immune-related genes. These germline variants were genotyped in IPI-treated melanoma patients, collected as part of a multi-institutional collaboration. We tested the association of ieQTLs with irAEs in a discovery cohort of 95 patients, followed by validation in an additional 97 patients.
Results: We found that the alternate allele of rs7036417, a variant linked to increased expression of SYK, was strongly associated with an increased risk of grade 3-4 toxicity [odds ratio (OR) = 7.46; 95% confidence interval (CI) = 2.65-21.03; p = 1.43E-04]. This variant was not associated with response (OR = 0.90; 95% CI = 0.37-2.21; p = 0.82).
Conclusion: We report that rs7036417 is associated with increased risk of severe irAEs, independent of IPI efficacy. SYK plays an important role in B-cell/T-cell expansion, and increased pSYK has been reported in patients with autoimmune disease. The association between rs7036417 and IPI irAEs in our data suggests a role of SYK overexpression in irAE development. These findings support the hypothesis that inherited variation in immune-related pathways modulates ICI toxicity and suggests SYK as a possible future target for therapies to reduce irAEs.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RF, VC, LM, DS, KM, EC, SZ, GM, MC, ES, IO and TK have no competing interests to report. AP: consultant for BMS, Merck and Regeneron. JL is on Data and Safety Monitoring Board (DSMB): Abbvie, Agenus, Amgen, Immutep and Evaxion; Scientific Advisory Board: (no stock) 7 Hills, Affivant, BioCytics, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio (stock) Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, physIQ, Pyxis, Saros, STipe and Tempest; consultancy with compensation: Abbvie, Agenus, Alnylam, Atomwise, Bayer, Bristol-Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Replimmune, Ribon, Roivant, Servier, STINGthera, Synlogic and Synthekine; research support: (all to institution for clinical trials unless noted) AbbVie, Astellas, Astrazeneca, Bristol-Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona and Xencor; patents: (both provisional) Serial #15/612657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). TFG is a consultant on advisory boards for Merck, Jounce, Fog Pharma, Adaptimmune, Pyxis, Allogene, Catalym, Bicara, Maia and Samyang; he has research support from BMS, Merck, Seattle Genetics, Evelo, Bayer and Pyxis; he has intellectual property/licensing with Aduro, Evelo and BMS and is a co-founder/shareholder for Jounce and Pyxis. PAA has/had consultant/advisory roles for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna and Bio-Al Health. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer and Sanofi; all of the above took place outside the submitted work. JW owns stock or other ownership at Altor BioScience, Biond, CytomX Therapeutics; received honoraria from Bristol-Myers Squibb, Merck, Genentech, AbbVie, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Eisai, Altor BioScience, Amgen, Roche, Ichor Medical Systems, Celldex, CytomX Therapeutics, Nektar, Novartis, Sellas, WindMIL and Takeda; has consulting/advisory role at Celldex, Ichor Medical Systems, Biond, Altor BioScience, Bristol-Myers Squibb, Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, AbbVie, Eisai, CytomX Therapeutics, Nektar, Novartis, Sellas, WindMIL and Takeda; obtained research funding (to the institution) from Bristol-Myers Squibb, Merck, GlaxoSmithKline, Genentech, Astellas Pharma, Incyte, Roche and Novartis; and received funding for travel/accommodations/expenses from Bristol-Myers Squibb, GlaxoSmithKline, Daiichi Sankyo, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech, Novartis, WindMIL and Takeda.
(Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)