Upregulation of intratumoral HLA class I and peritumoral Mx1 in ulcerated melanomas

Abstract

Before the era of immune checkpoint blockade, a meta-analysis encompassing fifteen trials reported that adjuvant IFN-α significantly reduces the risk of relapse and improves survival of ulcerated melanoma (UM) with no benefit for higher doses compared to lower doses. IFNa2b affects many cell intrinsic features of tumor cells and modulates the host innate and cognate immune responses. To better understand the biological traits associated with ulceration that could explain the efficacy of prophylactic type 1 IFN, we performed immunohistochemical analysis of various molecules (major histocompatibility complex class I and class II, MX Dynamin Like GTPase 1 (MX1), inducible Nitric-Oxide Synthase (iNOS) or CD47) in two retrospective cohorts of melanoma patients, one diagnosed with a primary cutaneous melanoma (1995-2013, N = 172, among whom 49% were ulcerated melanoma (UM)) and a second one diagnosed with metastatic melanoma amenable to lymph node resection (EORTC 18952 and 18991 trials, N = 98, among whom 44% were UM). We found that primary and metastatic UM exhibit higher basal expression of MHC class I molecules, independently of Breslow thickness, histology and lymphocytic infiltration compared with NUM and that primary UM harbored higher constitutive levels of the antiviral protein Mx1 at the border of tumor beds than NUM. These findings suggest that UM expand in a tumor microenvironment where chronic exposure to type 1 IFN could favor a response to exogenous IFNs.

The prognostic impact of the extent of ulceration in patients with clinical stage I– II melanoma: a multicentre study of the Italian Melanoma Intergroup ( IMI )

“…Different hypotheses have been proposed to explain the detrimental effect of ulceration: (i) ulceration-induced inflammation directly favours the induction of tumour-cell dispersal and a migratory-cell transition by modifying the local immune microenvironment; (ii) ulcerated melanoma represents a melanoma subtype with a specific gene profile and intrinsic cell with more proliferative properties favouring dissemination; 14,24,26,27 and (iii) ulceration induces suppression of adaptive immunity 28 through different mechanisms including the presence of lower mature dendritic cell densities, 29 and the overexpression of genes encoding the proinflammatory cytokines, which, in turn, are reported to play a major role in tumour-related inflammation. 30 Additional insights into the dynamic interplay of tumour cells and immune cells under the influence of proinflammatory cytokines and inflammationlinked transcription factors and proteases are needed for a better understanding of this complex phenomenon.…”

Ulcerated Cutaneous Melanoma: A Review of the Clinical, Histologic, and Molecular Features Associated with a Clinically Aggressive Histologic Phenotype

“…Major Histocompatibility Complex (MHC) I (HLA Class I) and MX Dynamin Like GTPase 1 (MX1) are proteins involved in tumor antigen presentation. 57 , 58 A study by Verver et al conducted IHC analysis for MHC I, MHC II, and MX1 in two retrospective cohorts of melanoma patients. Cohort 1 was diagnosed with a primary cutaneous melanoma (n = 172, 49% ulcerated melanoma).…”

“…The altered tumor microenvironment presents an opportunity for immune-based therapies and helps to explain why ulcerated primary melanomas seem to exclusively benefit from adjuvant IFN. 57 …”