Immunologic heterogeneity of tumor infiltrating lymphocyte composition in primary melanoma

• Published in: Human pathology Vol. 57; pp. 116 - 125
• Main Authors: Weiss, Sarah A., MD, Han, Sung Won, PhD, Lui, Kevin, MS, Tchack, Jeremy, BA, Shapiro, Richard, MD, Berman, Russell, MD, Zhong, Judy, PhD, Krogsgaard, Michelle, PhD, Osman, Iman, MD, Darvishian, Farbod, MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2016; Elsevier Limited
• Subjects: Aged; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Brisk; Cancer; CD3 Complex - analysis; Disease-Free Survival; Female; Forkhead Transcription Factors - analysis; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Host immune response; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Laboratories; Leukocyte Common Antigens - analysis; Lymphocytes, Tumor-Infiltrating - immunology; Male; Medical prognosis; Melanoma; Melanoma - genetics; Melanoma - immunology; Melanoma - pathology; Melanoma - therapy; Neoplasm Grading; Pathology; Patients; Phenotype; Prognosis; Proportional Hazards Models; Skin Neoplasms - genetics; Skin Neoplasms - immunology; Skin Neoplasms - pathology; Skin Neoplasms - therapy; Studies; Time Factors; Treatment Outcome; Tumor-infiltrating lymphocytes; host immune response; IHC; tumor infiltrating lymphocyte; formalin-fixed paraffin embedded; high power field; Institutional Review Board; American Joint Committee on Cancer; SLN; FFPE; recurrence-free survival; tumor infiltrating lymphocytes; AJCC; overall survival; immunohistochemistry; RFS; hematoxylin and eosin; T regulatory cell; OS; CI; H&E; Treg; Interdisciplinary Melanoma Cooperative Group; sentinel lymph node; melanoma; IMCG; NYU; prognosis; vertical growth phase; Integrative Pathway Analysis; TIL; IRB; New York University; confidence interval; IPA; VGP; HPF; Prognosis; Tumor-infiltrating lymphocytes; Brisk; Melanoma; Host immune response
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2016.07.008

Tumor infiltrating lymphocytes (TILs) in primary melanomas are thought to represent the host anti-tumor immune response, but controversy exists over whether TILs offer independent prognostication of survival. We studied a cohort of 1241 primary melanoma patients to assess the association of absent, non-brisk, 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 to histology alone in 15% of the cohort. To assess for inter-group 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%), non-brisk (n = 330, 27%), and brisk (n = 523, 42%). Patients with brisk TILs had improved recurrence-free survival (RFS) (P = .025) and overall survival (OS) (P = .006) compared to patients with non-brisk and absent TILs, for which there were no differences in RFS (P = .40) or OS (P = .41). TIL quantitation by immunohistochemistry did not improve prognostication compared to TIL grading on hematoxylin and eosin stained sections. Melanomas with non-brisk 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 to melanomas with non-brisk or absent TILs.