title: Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.
abstract: Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non-small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti-PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti-PD-1 therapy.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY, 10065, USA. chant@mskcc.org.
authors.forename: Naiyer A
authors.initials: NA
authors.lastname: Rizvi
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY, 10065, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hellmann
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY, 10065, USA. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Snyder
authors.affiliation: Division of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Pia
authors.initials: P
authors.lastname: Kvistborg
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Makarov
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Havel
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: William
authors.initials: W
authors.lastname: Lee
authors.affiliation: Immune Monitoring Core, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jianda
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Immune Monitoring Core, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Wong
authors.affiliation: Immune Monitoring Core, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Ho
authors.affiliation: Computation Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Miller
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Rekhtman
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Andre L
authors.initials: AL
authors.lastname: Moreira
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Fawzia
authors.initials: F
authors.lastname: Ibrahim
authors.affiliation: Department of Mathematics, Columbia University, New York, NY, 10027, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Bruggeman
authors.affiliation: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Billel
authors.initials: B
authors.lastname: Gasmi
authors.affiliation: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Zappasodi
authors.affiliation: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Computation Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.affiliation: David Geffen School of Medicine at UCLA, 2825 Santa Monica Boulevard, Suite 200, Santa Monica, CA 90404, USA.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Garon
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY, 10065, USA. Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: Division of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Ton N
authors.initials: TN
authors.lastname: Schumacher
authors.affiliation: Weill Cornell Medical College, New York, NY, 10065, USA. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. chant@mskcc.org.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D015331:Cohort Studies; D004260:DNA Repair / Q000235:genetics; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D009154:Mutation; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D012907:Smoking / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab