MHC class I molecules act as tumor suppressor genes regulating the cell cycle gene expression, invasion and intrinsic tumorigenicity of melanoma cells

Abstract

The alteration of MHC class I (MHC-I) expression is a frequent event during cancer progression, allowing tumor cells to evade the immune system. We report that the loss of one major histocompatibility complex haplotype in human melanoma cells not only allowed them to evade immunosurveillance but also increased their intrinsic oncogenic potential. A second successive defect in MHC-I expression, MHC-I total downregulation, gave rise to melanoma cells that were more oncogenic per se in vivo and showed a higher proliferation rate and greater migratory and invasive potential in vitro. All these processes were reversed by restoring MHC-I expression via human leukocite antigen-A2 gene transfection. MHC-I cell surface expression was inversely correlated with intrinsic oncogenic potential. Modifications in the expression of various cell cycle genes were correlated with changes in MHC-I expression; the most important differences among the melanoma cell lines were in the transcriptional level of AP2-alpha, cyclin A1 and p21WAF1/CIP1. According to these results, altered MHC-I expression in malignant cells can directly increase their intrinsic oncogenic and invasive potential and modulate the expression of cell cycle genes. These findings suggest that human leukocite antigen class I molecules may act directly as tumor suppressor genes in melanoma.

T Lymphocytes Restrain Spontaneous Metastases in Permanent Dormancy

“…However, other subpopulations of T cells should also be implicated, because the results found in CD8-versus asialo GM1-depleted tumor-bearing mice were different. In addition, we would highlight that MHC-I molecules can act directly as tumor suppressor genes, arresting cancer cell proliferation (48), and the FHIT tumor suppressor gene is directly implicated in MHC-I cell surface expression (30). Taken together, these results suggest that the expression of MHC-I molecules on these metastatic cells may promote the dormant state via immunomediated and oncogenic suppression mechanisms.…”

The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4

“…EGFR ligands, such as TGFA, EREG, and AREG, can activate EGFR, promote tumor metastasis, and enhance regulatory T cell-suppressive function via the EGFR (29). HLA-class I molecules are often downregulated or lost in tumor cells and play a key role in immune escape (30)(31)(32). A study by Carreteto and colleagues (33) showed that higher HLA class I gene expression was observed in regressing but not in progressing metastases from microdissected tumor regions, supporting the idea that the nature of HLA class I alterations in tumor cells may contribute to antitumor effects of therapeutic interventions.…”

Genetic Evolution of T-cell Resistance in the Course of Melanoma Progression

“…Besides, T-cell-independent mechanisms should also be taken into consideration. Recently, Garrido and colleagues demonstrated that HLA class I-negative melanoma cells showed enhanced proliferation, migration, and invasion in comparison with their HLA class I-positive counterparts, pointing to HLA class I molecules as tumor suppressors (42). Irrespective of the driving force, HLA class I alterations, in particular HLA class I loss, impede T-cell recognition of melanoma and will negatively influence all T-cell-based immunotherapies.…”