title: Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance.
abstract: Immune checkpoint blockade produces clinical benefit in many patients. However, better biomarkers of response are still needed, and mechanisms of resistance remain incompletely understood. To address this, we recently studied a cohort of melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) and identified immune markers of response and resistance. Building on these studies, we performed deep molecular profiling including T cell receptor sequencing and whole-exome sequencing within the same cohort and demonstrated that a more clonal T cell repertoire was predictive of response to PD-1 but not CTLA-4 blockade. Analysis of CNAs identified a higher burden of copy number loss in nonresponders to CTLA-4 and PD-1 blockade and found that it was associated with decreased expression of genes in immune-related pathways. The effect of mutational load and burden of copy number loss on response was nonredundant, suggesting the potential utility of a combinatorial biomarker to optimize patient care with checkpoint blockade therapy.
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Cancer Biology Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
authors.forename: Whijae
authors.identifier: 0000-0002-7395-9939
authors.initials: W
authors.lastname: Roh
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Pei-Ling
authors.identifier: 0000-0002-4600-0052
authors.initials: PL
authors.lastname: Chen
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Alexandre
authors.identifier: 0000-0003-4510-0382
authors.initials: A
authors.lastname: Reuben
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Christine N
authors.identifier: 0000-0002-3287-0292
authors.initials: CN
authors.lastname: Spencer
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Prieto
authors.affiliation: Oncology Research for Biologics and Immunotherapy Translation, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: John P
authors.identifier: 0000-0002-3405-2576
authors.initials: JP
authors.lastname: Miller
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Vancheswaran
authors.identifier: 0000-0002-8704-035X
authors.initials: V
authors.lastname: Gopalakrishnan
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Zachary A
authors.identifier: 0000-0003-1059-0940
authors.initials: ZA
authors.lastname: Cooper
authors.affiliation: Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Sangeetha M
authors.initials: SM
authors.lastname: Reddy
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Curtis
authors.identifier: 0000-0001-8026-0897
authors.initials: C
authors.lastname: Gumbs
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Latasha
authors.identifier: 0000-0001-9690-6314
authors.initials: L
authors.lastname: Little
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Wei-Shen
authors.identifier: 0000-0002-3637-7948
authors.initials: WS
authors.lastname: Chen
authors.affiliation: Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Khalida
authors.initials: K
authors.lastname: Wani
authors.affiliation: Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Pathology Department, A.C.Camargo Cancer Center, São Paulo, SP-01509-010, Brazil.
authors.forename: Mariana Petaccia
authors.initials: MP
authors.lastname: De Macedo
authors.affiliation: Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Eveline
authors.identifier: 0000-0001-8967-3890
authors.initials: E
authors.lastname: Chen
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jacob L
authors.identifier: 0000-0002-4841-6588
authors.initials: JL
authors.lastname: Austin-Breneman
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jason
authors.identifier: 0000-0002-4561-6170
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authors.lastname: Roszik
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Michael T
authors.identifier: 0000-0001-7899-4138
authors.initials: MT
authors.lastname: Tetzlaff
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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authors.initials: MA
authors.lastname: Davies
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jeffrey E
authors.identifier: 0000-0003-4519-5369
authors.initials: JE
authors.lastname: Gershenwald
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hussein
authors.identifier: 0000-0003-1942-851X
authors.initials: H
authors.lastname: Tawbi
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Alexander J
authors.identifier: 0000-0002-6395-4499
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Patrick
authors.identifier: 0000-0003-0554-2856
authors.initials: P
authors.lastname: Hwu
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Wen-Jen
authors.identifier: 0000-0003-1674-0751
authors.initials: WJ
authors.lastname: Hwu
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Adi
authors.identifier: 0000-0002-0153-0244
authors.initials: A
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authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Isabella C
authors.identifier: 0000-0002-4530-7765
authors.initials: IC
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authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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authors.identifier: 0000-0001-9204-7161
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authors.affiliation: Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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authors.affiliation: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.|Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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authors.affiliation: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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authors.affiliation: University of Texas System, Austin, TX 78701, USA.
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authors.affiliation: Applied Cancer Science Institute, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. afutreal@mdanderson.org jwargo@mdanderson.org.|Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
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authors.identifier: 0000-0003-3438-7576
authors.initials: JA
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authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. afutreal@mdanderson.org jwargo@mdanderson.org.
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authors.identifier: 0000-0001-8663-2671
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mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D001706:Biopsy; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002999:Clone Cells; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D018628:Gene Dosage; D016678:Genome; D006801:Humans; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D014408:Biomarkers, Tumor; D060908:CTLA-4 Antigen; D061026:Programmed Cell Death 1 Receptor