title: Impact of aging on host immune response and survival in melanoma: an analysis of 3 patient cohorts.
abstract: Age has been reported as an independent prognostic factor for melanoma-specific survival (MSS). We tested the hypothesis that age impacts the host anti-tumor immune response, accounting for age-specific survival outcomes in three unique melanoma patient cohorts.
  
  
  
  We queried the U.S. population-based Surveillance, Epidemiology, and End Results Program (SEER), the prospective tertiary care hospital-based Interdisciplinary Melanoma Cooperative Group (IMCG) biorepository, and the Cancer Genome Atlas (TCGA) biospecimen database to test the association of patient age at time of melanoma diagnosis with clinicopathologic features and survival outcomes. Age groups were defined as ≤45 (young), 46-65 (intermediate), and >65 (older). Each age group in the IMCG and TCGA cohorts was stratified by tumor infiltrating lymphocyte (TIL) measurements and tested for association with MSS. Differential expression of 594 immunoregulatory genes was assessed in a subset of primary melanomas in the IMCG and TCGA cohorts using an integrative pathway analysis.
  
  
  
  We analyzed 304, 476 (SEER), 1241 (IMCG), and 292 (TCGA) patients. Increasing age at melanoma diagnosis in both the SEER and IMCG cohorts demonstrated a positive correlation with tumor thickness, ulceration, stage, and mortality, however age in the TCGA cohort did not correlate with mortality. Older age was associated with shorter MSS in all three cohorts. When the young age group in both the IMCG and TCGA cohorts was stratified by TIL status, there were no differences in MSS. However, older IMCG patients with brisk TILs and intermediate aged TCGA patients with high lymphocyte scores (3-6) had improved MSS. Gene expression analysis revealed top pathways (T cell trafficking, communication, and differentiation) and top upstream regulators (CD3, CD28, IFNG, and STAT3) that significantly changed with age in 84 IMCG and 43 TCGA primary melanomas.
  
  
  
  Older age at time of melanoma diagnosis is associated with shorter MSS, however age's association with clinicopathologic features is dependent upon specific characteristics of the study population. TIL as a read-out of the host immune response may have greater prognostic impact in patients older than age 45. Recognition of age-related factors negatively impacting host immune responses may provide new insights into therapeutic strategies for the elderly.
authors.affiliation: Department of Medicine, NYU School of Medicine, New York, NY, USA.|Interdisciplinary Melanoma Cooperative Group, NYU School of Medicine, New York, NY, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Weiss
authors.affiliation: NYU School of Medicine, New York, NY, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Han
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, NYU School of Medicine, New York, NY, USA.|Department of Pathology, NYU School of Medicine, New York, NY, USA.
authors.forename: Farbod
authors.initials: F
authors.lastname: Darvishian
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, NYU School of Medicine, New York, NY, USA.|Ronald O. Perelman Department of Dermatology, NYU School of Medicine, New York, NY, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Tchack
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, NYU School of Medicine, New York, NY, USA.|Division of Biostatistics, Department of Population Health, NYU School of Medicine, 650 First Ave., Room 512, New York, NY, 10016, USA.|American Express, New York, NY, USA.
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Han
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY, USA.|School of Industrial Management Engineering, Korea University, Seoul, South Korea.
authors.forename: Karolina
authors.initials: K
authors.lastname: Malecek
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, NYU School of Medicine, New York, NY, USA.|Department of Pathology, NYU School of Medicine, New York, NY, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Krogsgaard
authors.affiliation: Department of Medicine, NYU School of Medicine, New York, NY, USA.|Interdisciplinary Melanoma Cooperative Group, NYU School of Medicine, New York, NY, USA.|Ronald O. Perelman Department of Dermatology, NYU School of Medicine, New York, NY, USA.
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.affiliation: Interdisciplinary Melanoma Cooperative Group, NYU School of Medicine, New York, NY, USA. Judy.Zhong@nyumc.org.|Division of Biostatistics, Department of Population Health, NYU School of Medicine, 650 First Ave., Room 512, New York, NY, 10016, USA. Judy.Zhong@nyumc.org.
authors.forename: Judy
authors.initials: J
authors.lastname: Zhong
mesh_terms: D000368:Aged; D000375:Aging / Q000473:pathology*; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007109:Immunity; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology*; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D011379:Prognosis; D018426:SEER Program; D016019:Survival Analysis
keywords: Age; Elderly; Host immune response; Melanoma; SEER; TCGA; Tumor infiltrating lymphocytes