Abstract
Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second.
Publication types
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Clinical Trial, Phase I
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Clinical Trial, Phase II
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Aged, 80 and over
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Antibodies, Monoclonal, Humanized / pharmacology
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Antibodies, Monoclonal, Humanized / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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B7-H1 Antigen / genetics*
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B7-H1 Antigen / immunology
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B7-H1 Antigen / metabolism
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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DNA Mutational Analysis
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Drug Monitoring / methods
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Female
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Gene Amplification
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Humans
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Indazoles / pharmacology
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Indazoles / therapeutic use
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Interferons / immunology
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Interferons / metabolism
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism
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Middle Aged
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Neoplasm Recurrence, Local / drug therapy*
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Neoplasm Recurrence, Local / genetics
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Neoplasm Recurrence, Local / immunology
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Neoplasm Recurrence, Local / pathology
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / immunology
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Ovarian Neoplasms / pathology
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Ovary / pathology
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Piperidines / pharmacology
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Piperidines / therapeutic use
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Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
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Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use*
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Programmed Cell Death 1 Ligand 2 Protein / genetics
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Programmed Cell Death 1 Ligand 2 Protein / metabolism
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Programmed Cell Death 1 Receptor / antagonists & inhibitors*
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Recombinational DNA Repair / genetics
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Single-Cell Analysis
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Treatment Outcome
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Tumor Microenvironment / drug effects
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Tumor Microenvironment / genetics
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Tumor Microenvironment / immunology
Substances
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Antibodies, Monoclonal, Humanized
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B7-H1 Antigen
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CD274 protein, human
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Indazoles
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PDCD1 protein, human
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PDCD1LG2 protein, human
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Piperidines
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Poly(ADP-ribose) Polymerase Inhibitors
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Programmed Cell Death 1 Ligand 2 Protein
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Programmed Cell Death 1 Receptor
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Interferons
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pembrolizumab
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niraparib
Associated data
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ClinicalTrials.gov/NCT02657889