title: Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma.
abstract: Immune checkpoint blockade is revolutionizing therapy for advanced cancer, but many patients do not respond to treatment. The identification of robust biomarkers that predict clinical response to specific checkpoint inhibitors is critical in order to stratify patients and to rationally select combinations in the context of an expanding array of therapeutic options.
  
  
  
  We performed multiparameter flow cytometry on freshly isolated metastatic melanoma samples from 2 cohorts of 20 patients each prior to treatment and correlated the subsequent clinical response with the tumor immune phenotype.
  
  
  
  Increasing fractions of programmed cell death 1 high/cytotoxic T lymphocyte-associated protein 4 high (PD-1hiCTLA-4hi) cells within the tumor-infiltrating CD8+ T cell subset strongly correlated with response to therapy (RR) and progression-free survival (PFS). Functional analysis of these cells revealed a partially exhausted T cell phenotype. Assessment of metastatic lesions during anti-PD-1 therapy demonstrated a release of T cell exhaustion, as measured by an accumulation of highly activated CD8+ T cells within tumors, with no effect on Tregs.
  
  
  
  Our data suggest that the relative abundance of partially exhausted tumor-infiltrating CD8+ T cells predicts response to anti-PD-1 therapy. This information can be used to appropriately select patients with a high likelihood of achieving a clinical response to PD-1 pathway inhibition.
  
  
  
  This work was funded by a generous gift provided by Inga-Lill and David Amoroso as well as a generous gift provided by Stephen Juelsgaard and Lori Cook.
authors.forename: Adil I
authors.initials: AI
authors.lastname: Daud
authors.forename: Kimberly
authors.initials: K
authors.lastname: Loo
authors.forename: Mariela L
authors.initials: ML
authors.lastname: Pauli
authors.forename: Robert
authors.initials: R
authors.lastname: Sanchez-Rodriguez
authors.forename: Priscila Munoz
authors.initials: PM
authors.lastname: Sandoval
authors.forename: Keyon
authors.initials: K
authors.lastname: Taravati
authors.forename: Katy
authors.initials: K
authors.lastname: Tsai
authors.forename: Adi
authors.initials: A
authors.lastname: Nosrati
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Nardo
authors.forename: Michael D
authors.initials: MD
authors.lastname: Alvarado
authors.forename: Alain P
authors.initials: AP
authors.lastname: Algazi
authors.forename: Miguel H
authors.initials: MH
authors.lastname: Pampaloni
authors.forename: Iryna V
authors.initials: IV
authors.lastname: Lobach
authors.forename: Jimmy
authors.initials: J
authors.lastname: Hwang
authors.forename: Robert H
authors.initials: RH
authors.lastname: Pierce
authors.forename: Iris K
authors.initials: IK
authors.lastname: Gratz
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Krummel
authors.forename: Michael D
authors.initials: MD
authors.lastname: Rosenblum
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D001706:Biopsy; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D060908:CTLA-4 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007107:Immune System; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D009362:Neoplasm Metastasis; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000166:cytology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human