Impact of aging on host immune response and survival in melanoma: an analysis of 3 patient cohorts

Abstract

BackgroundAge 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.MethodsWe 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.ResultsWe 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.ConclusionsOlder 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1026-2) contains supplementary material, which is available to authorized users.

Enhanced expression of PD-1 and other activation markers by CD4+ T cells of young but not old patients with metastatic melanoma

“…We are aware that our findings do not necessarily reflect immune responses at the tumor site in melanoma patients. Brisk tumor-infiltrating lymphocytes and high lymphocyte tumor distribution and density in melanoma are associated with improved disease-specific survival [ 29 ]. A study with tumor tissue samples from 147 metastatic melanoma patients showed an independent positive association between overall survival and higher counts of CD8+ T cells and PD-1 expressing cells [ 30 ].…”

Skin Cancer Epidemics in the Elderly as An Emerging Issue in Geriatric Oncology

“…The progressive impairment of both innate and adaptive immunity affects responses to pathogens, and vaccines as wells as anti-tumour surveillance [ 84 ]. Evidence of an aging-related T-cell dysfunction has been recently reported in gene-expression studies of different melanoma-patient cohorts [ 85 ]. Tumour-infiltrating lymphocytes (TILs) in primary melanoma represent a known pathological, albeit surrogate, marker of the host anti-tumour immune response.…”

Histopathologic variables differentially affect melanoma survival by age at diagnosis

“…Older patients tend to present with primary tumors with aggressive features and have an overall poorer prognosis when compared to younger patients (Balch et al, ; Cavanaugh‐Hussey, Mu, Kang, Balch, & Wang, ; Hoag et al, ). Age‐related comorbidities, weakening immunity, and delivery of care may be partly contributing to this trend (Rees et al, ; Weiss et al, ). Here, we use a population‐based case–control study with 20‐year survival data to investigate characteristics that are associated with melanoma survival in older patients (those 56 years or older) compared to younger patients (those <56 years).…”