Current Status and Molecular Mechanisms of Resistance to Immunotherapy in Oral Malignant Melanoma

Abstract

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies, have initiated a new era in the treatment of malignant melanoma. ICIs can be used in various settings, including first-line, adjuvant, and neo-adjuvant therapy. In the scope of this review, we examined clinical studies utilizing ICIs in the context of treating oral mucosal melanoma, a rare disease, albeit with an extremely poor prognosis, with a specific focus on unraveling the intricate web of resistance mechanisms. The absence of a comprehensive review focusing on ICIs in oral mucosal melanoma is notable. Therefore, this review seeks to address this deficiency by offering a novel and thorough analysis of the current status, potential resistance mechanisms, and future prospects of applying ICIs specifically to oral malignant melanoma. Clarifying and thoroughly understanding these mechanisms will facilitate the advancement of effective therapeutic approaches and enhance the prospects for patients suffering from oral mucosal melanoma.

Keywords: anti-CTLA-4; anti-PD-1; immune checkpoint blockade; immune checkpoint inhibitor; immunotherapy; melanoma; oral mucosal melanoma; resistance mechanism.

Figure 1

The intrinsic mechanism underlying the resistance to immune checkpoint blockade in melanoma cells. This intrinsic mechanism includes the following elements: 1. alterations in signaling pathways, transcription factors, and regulatory networks; 2. the lack of antigenic mutations/neoantigens; and 3. defects in the antigen processing and presenting systems. The upregulation of the MAPK pathway can contribute to resistance by increasing the PDL-1 expression, impairing T-cell infiltration and, inducing the acquisition of a mesenchymal phenotype by melanoma cells. The activation of the β-catenin pathway leads to T-cell exclusion and resistance, as does the loss of PTEN and the upregulation of the transcription factor ZEB1. The lack of tumor antigens and antigenic mutations poses a barrier to the immune system’s ability to recognize tumor cells. A regulatory network dependent on TCF4/BRD4 not only hinders antigen presentation, interferon signaling, and the activation of leukocyte-associated gene expression but also supports the acquisition of a mesenchymal phenotype, leading to resistance. For an effective immune response, tumor antigens need to be presented to the immune system. The dysregulation of MHC-1, B2M, and TAP in the antigen processing and presenting machinery hinders proper antigen presentation, thereby impeding a robust immune response. Interferon-gamma plays a dual role in resistance mechanisms by upregulating both MHC-1 and MHC-2, contributing to antigen processing and presenting machinery, while also leading to PD-L1 expression. Abbreviations: MHC, major histocompatibility complex; TAP, the transporter associated with antigen processing; B2M, beta-2-microglobulin; IFN-γ, interferon-gamma; MAPK, mitogen-activated protein kinases; PTEN, phosphatase and tensin homolog; ZEB1, zinc finger E-box-binding homeobox 1; ER, endoplasmic reticulum.

Figure 2

The extrinsic mechanism underlying the resistance to immune checkpoint blockade. This mechanism of resistance to immune checkpoint blockade includes extrinsic (A) immune-suppressive cell components, such as regulatory T cells (Treg), tumor-associated macrophages (TAMs), regulatory/tolerogenic dendritic cells (DC), and myeloid-derived suppressor cells (MDSC); (B) various inhibitory receptors, such as PDL-1, CTLA-4, LAG-3, TIMS-3, and VISTA; (C) hypoxic tumor microenvironment; and (D) phenotype switching. Abbreviations: LAG-3, lymphocyte-activation gene 3; PDL-1, programmed death ligand 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; TIM-3, T-cell immunoglobulin and mucin domain 3; VISTA, V-domain I g suppressor of T cell activation; HIF-1α, hypoxia-inducible factor 1-alpha; MITF, microphthalmia-associated transcription factor.