title: Immunologic heterogeneity of tumor-infiltrating lymphocyte composition in primary melanoma.
abstract: Tumor-infiltrating lymphocytes (TILs) in primary melanomas are thought to represent the host antitumor immune response, but controversy exists over whether TILs offer independent prognostication of survival. We studied a cohort of 1241 patients with primary melanoma to assess the association of absent, nonbrisk, and brisk TIL grade with survival outcomes. We tested whether quantitative TIL counts using immunohistochemical lymphocyte markers CD3, CD45, and FOXP3 add prognostic value to TIL grading compared with histology alone in 15% of the cohort. To assess for intergroup immunologic heterogeneity among TIL grades, we investigated differential expression of 594 immunoregulatory genes in 67 primary melanomas. On histologic evaluation of 1241 primary melanomas, TILs were graded as absent (n=388, 31%), nonbrisk (n=330, 27%), and brisk (n=523, 42%). Patients with brisk TILs had improved recurrence-free survival (P=.025) and overall survival (P=.006) compared with patients with nonbrisk and absent TILs, for which there were no differences in recurrence-free survival (P=.40) or overall survival (P=.41). TIL quantitation by immunohistochemistry did not improve prognostication compared with TIL grading on hematoxylin and eosin-stained sections. Melanomas with nonbrisk and absent TILs share similar immunoregulatory gene expression profiles. In contrast, melanomas with brisk TILs demonstrate upregulation of T-cell activation pathways and inhibition of upstream immune checkpoint regulators. The presence of TILs in primary melanomas represents a heterogeneous group, and caution in prognostic interpretation is warranted. Melanomas with brisk TILs are defined by an immunostimulatory gene expression profile and improved prognosis compared with melanomas with nonbrisk or absent TILs.
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, NY, USA 10016; Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA 10016. Electronic address: Sarah.Weiss@nyumc.org.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Weiss
authors.affiliation: Department of Population Health, New York University School of Medicine, New York, NY, USA 10016. Electronic address: sungwonhan2@gmail.com.
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Han
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA 10016; Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA 10016. Electronic address: kevin.paul.lui@gmail.com.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lui
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA 10016; Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA 10016. Electronic address: Jeremy.Tchack@nyumc.org.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Tchack
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA 10016; Department of Surgery, New York University School of Medicine, New York, NY, USA 10016. Electronic address: Richard.Shapiro@nyumc.org.
authors.forename: Richard
authors.initials: R
authors.lastname: Shapiro
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA 10016; Department of Surgery, New York University School of Medicine, New York, NY, USA 10016. Electronic address: Russell.Berman@nyumc.org.
authors.forename: Russell
authors.initials: R
authors.lastname: Berman
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA 10016; Department of Biostatistics, New York University School of Medicine, New York, NY, USA 10016. Electronic address: Judy.Zhong@nyumc.org.
authors.forename: Judy
authors.initials: J
authors.lastname: Zhong
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA 10016; Department of Pathology, New York University School of Medicine, New York, NY, USA 10016. Electronic address: Michelle.Krogsgaard@nyumc.org.
authors.forename: Michelle
authors.initials: M
authors.lastname: Krogsgaard
authors.affiliation: Department of Medicine, New York University School of Medicine, New York, NY, USA 10016; Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA 10016; Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA 10016. Electronic address: Iman.Osman@nyumc.org.
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA 10016; Department of Pathology, New York University School of Medicine, New York, NY, USA 10016. Electronic address: Farbod.Darvishian@nyumc.org.
authors.forename: Farbod
authors.initials: F
authors.lastname: Darvishian
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D017252:CD3 Complex / Q000032:analysis; D018572:Disease-Free Survival; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D017493:Leukocyte Common Antigens / Q000032:analysis; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D060787:Neoplasm Grading; D010641:Phenotype; D016016:Proportional Hazards Models; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D017252:CD3 Complex; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human
keywords: Brisk; Host immune response; Melanoma; Prognosis; Tumor-infiltrating lymphocytes