title: Multiparametric profiling of non-small-cell lung cancers reveals distinct immunophenotypes.
abstract: BACKGROUND.Immune checkpoint blockade improves survival in a subset of patients with non-small-cell lung cancer (NSCLC), but robust biomarkers that predict response to PD-1 pathway inhibitors are lacking. Furthermore, our understanding of the diversity of the NSCLC tumor immune microenvironment remains limited.METHODS.We performed comprehensive flow cytometric immunoprofiling on both tumor and immune cells from 51 NSCLCs and integrated this analysis with clinical and histopathologic characteristics, next-generation sequencing, mRNA expression, and PD-L1 immunohistochemistry (IHC).RESULTS.Cytometric profiling identified an immunologically "hot" cluster with abundant CD8+T cells expressing high levels of PD-1 and TIM-3 and an immunologically "cold" cluster with lower relative abundance of CD8+T cells and expression of inhibitory markers. The "hot" cluster was highly enriched for expression of genes associated with T cell trafficking and cytotoxic function and high PD-L1 expression by IHC. There was no correlation between immunophenotype and KRAS or EGFR mutation, or patient smoking history, but we did observe an enrichment of squamous subtype and tumors with higher mutation burden in the "hot" cluster. Additionally, approximately 20% of cases had high B cell infiltrates with a subset producing IL-10.CONCLUSIONS.Our results support the use of immune-based metrics to study response and resistance to immunotherapy in lung cancer.FUNDING.The Robert A. and Renée E. Belfer Family Foundation, Expect Miracles Foundation, Starr Cancer Consortium, Stand Up to Cancer Foundation, Conquer Cancer Foundation, International Association for the Study of Lung Cancer, National Cancer Institute (R01 CA205150), and the Damon Runyon Cancer Research Foundation.
authors.affiliation: Belfer Center for Applied Cancer Science, Boston, Massachusetts, USA.|Department of Medical Oncology and.
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Lizotte
authors.affiliation: Belfer Center for Applied Cancer Science, Boston, Massachusetts, USA.|Department of Medical Oncology and.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Ivanova
authors.affiliation: Department of Medical Oncology and.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Awad
authors.affiliation: Belfer Center for Applied Cancer Science, Boston, Massachusetts, USA.|Department of Medical Oncology and.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Jones
authors.affiliation: Belfer Center for Applied Cancer Science, Boston, Massachusetts, USA.|Department of Medical Oncology and.
authors.forename: Lauren
authors.initials: L
authors.lastname: Keogh
authors.affiliation: Belfer Center for Applied Cancer Science, Boston, Massachusetts, USA.|Department of Medical Oncology and.
authors.forename: Hongye
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology and.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Dries
authors.affiliation: Department of Medical Oncology and.
authors.forename: Christina
authors.initials: C
authors.lastname: Almonte
authors.affiliation: Department of Medical Oncology and.
authors.forename: Grit S
authors.initials: GS
authors.lastname: Herter-Sprie
authors.affiliation: Department of Medical Oncology and.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Santos
authors.affiliation: Belfer Center for Applied Cancer Science, Boston, Massachusetts, USA.|Department of Medical Oncology and.
authors.forename: Nora B
authors.initials: NB
authors.lastname: Feeney
authors.affiliation: Belfer Center for Applied Cancer Science, Boston, Massachusetts, USA.|Department of Medical Oncology and.
authors.forename: Cloud P
authors.initials: CP
authors.lastname: Paweletz
authors.affiliation: Belfer Center for Applied Cancer Science, Boston, Massachusetts, USA.|Department of Medical Oncology and.
authors.forename: Meghana M
authors.initials: MM
authors.lastname: Kulkarni
authors.affiliation: Department of Medical Oncology and.|Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
authors.affiliation: Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Guo-Cheng
authors.initials: GC
authors.lastname: Yuan
authors.affiliation: Department of Medical Oncology and.|Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Kufe
authors.affiliation: Belfer Center for Applied Cancer Science, Boston, Massachusetts, USA.|Department of Medical Oncology and.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: Department of Medical Oncology and.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: Harvard Medical School, Boston, Massachusetts, USA.|Department of Pathology.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.affiliation: Department of Medical Oncology and.|Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Harvard Medical School, Boston, Massachusetts, USA.|Division of Thoracic Surgery, and.|International Mesothelioma Program of the Lung Center Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.affiliation: Harvard Medical School, Boston, Massachusetts, USA.|Division of Thoracic Surgery, and.|International Mesothelioma Program of the Lung Center Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Bueno
authors.affiliation: Belfer Center for Applied Cancer Science, Boston, Massachusetts, USA.|Department of Medical Oncology and.
authors.forename: Jessie M
authors.initials: JM
authors.lastname: English
authors.affiliation: Belfer Center for Applied Cancer Science, Boston, Massachusetts, USA.|Department of Medical Oncology and.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bittinger
authors.affiliation: Belfer Center for Applied Cancer Science, Boston, Massachusetts, USA.|Department of Medical Oncology and.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D060890:B7-H1 Antigen / Q000276:immunology; D014408:Biomarkers, Tumor / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000145:classification*; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D008168:Lung; D008175:Lung Neoplasms / Q000145:classification*; D009154:Mutation
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human