Anti-PD-1 treatment have achieved advanced success in malignant melanoma. While the expression of valuable markers, such as TMB, MSI, and PD-L1, could serve as effective predictors of anti-checkpoint inhibitor therapies, not all melanoma patients are effective to this treatment. In a recent study, the objective response rate (ORR) is 41% in all melanoma patients and 52% for treatment-naive melanoma patients [5]. Additionally, treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8% of patients; 17% experienced grade 3/4 TRAE [5]. Although immunotherapy has greatly improved the prognosis of patients, immunotherapy remains largely ineffective in patients with tumors not infiltrated by immune cells. In order to incrementally advance the immunotherapeutic options in melanoma treatment, the discovery of new therapeutic methods and/or adjuvants that target multiple cellular processes shows special significance.
Previous studies have reported that MIIP plays a role as a tumor suppressor gene. In gliomas, through binding to HDAC6, highly expressed MIIP causes decreased HDAC6 expression and inhibition of HDAC6 deacetylase activity, thereby inhibiting HDAC6-mediated cell migration [19]. The tumor suppressor function of MIIP has been demonstrated in tissues from breast cancer [30] and colorectal cancer [31]. In the current study, we verified that melanoma patients exhibited a negative MIIP expression and predicted worse overall survival when compared with patients with a positive MIIP expression. We also found the positive expression of HDAC6, a molecule that is downstream of MIIP, had a positive trend with decreased overall survival, because the p value was not statistically significant. The reason for this inconsistency may be due to our insufficient sample size and rough melanoma subtype classification. We will collect more samples and perform more precise subtype classification to explore the role of HDAC6 in melanoma. At the same time, the positive expression of PD-L1, an important costimulatory molecule expressed in cancer cells, was associated with worse overall survival. Furthermore, there was a positive association between HDAC6 and PD-L1.
When we studied the relationship between the expression levels of MIIP, HDAC6 and PD-L1 and the clinicopathological factors in melanoma patients, a correlation between PD-L1 and melanoma cell Clark stage was identified. The expression rate of PD-L1 was significantly greater in higher Clark levels [82.8% (53/64)] than it was in lower Clark levels [56.5% (39/69)] (chi-square test, p < 0.01). The Clark stage classification is defined by measuring the depth of skin invasion of melanoma cell to the anatomical level. And it provides a correlation between the degree of skin invasion by melanoma and the 5-year survival rate after surgery. In malignant melanoma, the relationship between PD-L1 expression and Clark stage may exhibit a greater likelihood of malignant behaviors. However, this needs further study for validation.
Some HDACs have received particular attention for their recently endowed roles in regulating tumorigenesis and immune response [32, 33]. However, HDACi's ability to regulate cellular immune microenvironment and their therapeutic potential as targeted agents combined with immunotherapy are not clear. Histone deacetylases (HDACs) and selective HDAC inhibitors (HDACi), alone or in combination with other anti-cancer agents, are promising therapeutic methods in many cancers [34–37]. As a major transcription factor regulating PD-L1, Lienlaf et al demonstrated that HDAC6 was crucial adjective for the recruitment and activation of STAT3 and the upregulation of PD-L1. Additionally, a study has demonstrated that in the mouse model of B16F10 immunotherapy, HDACi combined with PD-1/PD-L1 checkpoint inhibitors can significantly improve the therapeutic effect of immunotherapy alone [38] In multiple myeloma, the expression of PD-L1 is immediately correlated with disease progression. By contrast, the highest PD-L1 expression was observed in patients with recurrent / refractory multiple myeloma.[39] ACY-241, the HDAC6 selective inhibitor, combined treatment with anti-PD-L1 treatment can enhance anti-multiple myeloma immunity in the bone marrow microenvironment through down-regulating the interaction between pDC-T cell and pDC-NK cell.[36] A recent study also showed that a HDAC6i, ricolinostat, promoted phenotypic changes that supported the activation of T cells and improved the function of antigen presenting cells.[40] Furthermore, The use of histone deacetylase 6 (HDAC6) inhibitors limited the growth of ovarian cancer with mutations in ARID1A, which is the most common mutations in human cancer epigenetic regulation factor; Mutations in ARID1A occur in more than 50% of ovarian clear cell carcinomas and it modulates the tumor immune microenvironment.[41] Regarding our present study which suggests that MIIP inhibits the expression of PD-L1 by downregulating the expression of HDAC6 in melanoma, methods that target MIIP-HDAC6-PD-L1 pathways, such as treatment with HDAC6, might provide a new therapeutic approach to enhance immune checkpoint inhibitor therapies in malignant melanoma.
In addition to HDAC6, MIIP can also regulate the expression of insulin-like growth factor-binding protein 2 (IGFBP2), and it can accelerate epidermal growth factor receptor (EGFR) protein turnover and attenuate proliferation [14, 20]. Accumulating evidence has suggested that IGFBP2 modulates the immune response in cancer patients and can be a potential target for cancer immunotherapy [42]. Although an IGFBP2 vaccine was shown to be immunosuppressive, removing the IL-10-inducing T helper epitopes from the vaccine was suggested to ensure potent IGFBP2 anti-tumor activity [43]. Furthermore, many clinical trials have investigated EGFR-mediated tumor immune escape as a target for immunotherapy through the use of immune checkpoint inhibitors. Concha-Benavente et al. (2013) found that overexpression of EGFR in response to IFN-γ through the JAK2/STAT1 pathway upregulated PD-L1 expression and that specific inhibition of JAK2 abolished PD-L1 upregulation in head and neck cancer. In another study, the mutated and constitutively active EGFR/KRAS-MAPK pathway was suggested to cause upregulation of PD-L1 in non-small-cell lung cancer [44]. However, as an upstream gene of IGFBP2, HDAC6 and EGFR, the mechanism of MIIP involvement in immune regulation requires further investigation.