title: Cytotoxic T Cells in PD-L1-Positive Malignant Pleural Mesotheliomas Are Counterbalanced by Distinct Immunosuppressive Factors.
abstract: PD-L1 immunohistochemical staining does not always predict whether a cancer will respond to treatment with PD-1 inhibitors. We sought to characterize immune cell infiltrates and the expression of T-cell inhibitor markers in PD-L1-positive and PD-L1-negative malignant pleural mesothelioma samples. We developed a method for immune cell phenotyping using flow cytometry on solid tumors that have been dissociated into single-cell suspensions and applied this technique to analyze 43 resected malignant pleural mesothelioma specimens. Compared with PD-L1-negative tumors, PD-L1-positive tumors had significantly more infiltrating CD45+immune cells, a significantly higher proportion of infiltrating CD3+T cells, and a significantly higher percentage of CD3+cells displaying the activated HLA-DR+/CD38+phenotype. PD-L1-positive tumors also had a significantly higher proportion of proliferating CD8+T cells, a higher fraction of FOXP3+/CD4+Tregs, and increased expression of PD-1 and TIM-3 on CD4+and CD8+T cells. Double-positive PD-1+/TIM-3+CD8+T cells were more commonly found on PD-L1-positive tumors. Compared with epithelioid tumors, sarcomatoid and biphasic mesothelioma samples were significantly more likely to be PD-L1 positive and showed more infiltration with CD3+T cells and PD-1+/TIM-3+CD8+T cells. Immunologic phenotypes in mesothelioma differ based on PD-L1 status and histologic subtype. Successful incorporation of comprehensive immune profiling by flow cytometry into prospective clinical trials could refine our ability to predict which patients will respond to specific immune checkpoint blockade strategies. Cancer Immunol Res; 4(12); 1038-48. ©2016 AACR.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Awad
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Jones
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Hongye
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Lizotte
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Ivanova
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Meghana
authors.initials: M
authors.lastname: Kulkarni
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Grit S
authors.initials: GS
authors.lastname: Herter-Sprie
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liao
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Abigail A
authors.initials: AA
authors.lastname: Santos
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bittinger
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Lauren
authors.initials: L
authors.lastname: Keogh
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Shohei
authors.initials: S
authors.lastname: Koyama
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Christina
authors.initials: C
authors.lastname: Almonte
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Jessie M
authors.initials: JM
authors.lastname: English
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.|Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Julianne
authors.initials: J
authors.lastname: Barlow
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.|Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: William G
authors.initials: WG
authors.lastname: Richards
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: David A
authors.initials: DA
authors.lastname: Barbie
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Kai W
authors.initials: KW
authors.lastname: Wucherpfennig
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.|Belfer Center for Applied Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. kwok-kin_wong@dfci.harvard.edu.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.|Belfer Center for Applied Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.|Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Raphael
authors.initials: R
authors.lastname: Bueno
mesh_terms: D060890:B7-H1 Antigen / Q000276:immunology*; D005260:Female; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000276:immunology*; D010997:Pleural Neoplasms / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human