Melanoma subtypes demonstrate distinct PD-L1 expression profiles

Abstract

PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-γ-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n = 16), mucosal (n = 36), uveal (n = 103), and chronic sun-damaged (CSD) (n = 45) melanomas (24 lentigo maligna, 13 ‘mixed’ desmoplastic, and 8 ‘pure’ desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P = 0.0002) and higher in CSD (P = 0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate–severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P = 0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype.

Use of immune checkpoint inhibitors prolonged overall survival in a Japanese population of advanced malignant melanoma patients: Retrospective single institutional study

“…However, our retrospective single‐institution study showed that the current patients who could afford immune checkpoint inhibitors had significantly improved OS when compared with the patients who were treated before immune checkpoint inhibitors became available. Surprisingly, this improvement was seen not only in patients with SSM, but also in those with ALM, the clinical type that is considered to respond poorly to immune checkpoint inhibitors . Therefore, immune checkpoint inhibitors may also improve the prognosis of Asian melanoma patients.…”

“…However, these previous studies comprised mainly white populations, in which SSM and LMM are the major clinical types of melanoma . In contrast, Asians manifest a distinct clinicopathological type of melanoma from that of whites and show much higher frequencies of ALM and MUC, which have been shown to be less susceptible to immune checkpoint inhibitors . Although αPD‐1mAb and ipilimumab have demonstrated their efficacy in single‐arm studies, no comparative studies have been published showing improvement of OS by immune checkpoint inhibitors in Asian melanoma patients.…”

Implications of the tumor immune microenvironment for staging and therapeutics

“…The adaptive pattern of PD-L1 expression also predominates in melanoma subtypes, such as ocular, desmoplastic, acral, and mucosal melanomas. 70 Adaptive PD-L1 expression is a positive prognostic feature when expressed by either tumor cells or tumor-associated immune cells. 7 Both melanocyte and immune cell PD-L1 display is primarily IFN- γ driven, though other cytokines such as interleukin10 may preferentially contribute to macrophage as opposed to tumor cell PD-L1 expression.…”

Pd-L1

“…The prevalence of PD-L1 expression in melanoma ranges from 24% to 49%,51–53 being highest (~60%) in tumours arising from chronic sun-damaged skin and lowest in uveal melanoma (10%) 54. PD-L1 independently predicts for poorer prognosis, being strongly correlated to tumour thickness, lymphatic and visceral spread, and in BRAF-mutant melanoma, PD-L1 overexpression is an adaptive feature of resistance to BRAF inhibitors 55 56.…”