Abstract
Although melanoma remains the deadliest skin cancer, the current treatment has not resulted in the desired outcomes. Unlike chemotherapy, immunotherapy has provided more tolerable approaches and revolutionized cancer therapy. Although dendritic cell-based vaccines have minor side effects, the undesirable response rates of traditional approaches have posed questions about their clinical translation. The immunosuppressive tumor microenvironment can be the underlying reason for their low response rates. Immune checkpoints and indoleamine 2,3-dioxygenase have been implicated in the induction of immunosuppressive tumor microenvironment. Growing evidence indicates that the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/Protein kinase B (PKB) (PI3K/AKT) pathways, as the main oncogenic pathways of melanoma, can upregulate the tumoral immune checkpoints, like programmed death-ligand 1. This study briefly represents the main oncogenic pathways of melanoma and highlights the cross-talk between these oncogenic pathways with indoleamine 2,3-dioxygenase, tumoral immune checkpoints, and myeloid-derived suppressor cells. Moreover, this study sheds light on a novel tumor antigen on melanoma, which has substantial roles in tumoral immune checkpoints expression, indoleamine 2,3-dioxygenase secretion, and stimulating the oncogenic pathways. Finally, this review collects the lessons from the previous unsuccessful trials and integrates their lessons with new approaches in RNA-modified dendritic cell vaccines. Unlike traditional approaches, the advances in single-cell RNA-sequencing techniques and RNA-modified dendritic cell vaccines along with combined therapy of the immune checkpoint inhibitors, indoleamine 2,3-dioxygenase inhibitor, and RNA-modified dendritic cell-based vaccine can overcome these auto-inductive loops and pave the way for developing robust dendritic cell-based vaccines with the most favorable response rate and the least side effects.
Highlights
Melanoma is the malignant proliferation of neural-crest-derived pigment-producing cells located in the skin, inner ear, eye, and leptomeninges [1]
This study aims to highlight the cross-talk between the main oncogenic pathways of melanoma and immunosuppressive inducer factors, i.e., tumoral immune checkpoints, myeloid-derived suppressor cells (MDSCs), and IDO
Recent findings have indicated that there is a synapse between various dendritic cells (DCs) to share tumor antigens [107], human DCs can be divided into plasmacytoid DC, conventional DC, and monocyte-derived DCs (MoDC) subsets
Summary
Melanoma is the malignant proliferation of neural-crest-derived pigment-producing cells located in the skin, inner ear, eye, and leptomeninges [1]. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) on the T-cells, and the related ligands on the DCs, i.e., CD80/86 and PD-L1/PD-L2, are the pivotal inhibitory signals that attenuate anti-tumoral immune responses [8] Targeting these inhibitory signals can pave the way for developing potent vaccines for melanoma patients [9]. Recent studies have demonstrated multiple interplays between melanoma oncogenic pathways, MUC1, the abovementioned tumoral immune checkpoints, MDSCs, and indoleamine 2,3dioxygenase (IDO). These auto-inductive loops can inhibit the development of anti-tumoral immune responses in the melanoma microenvironment. This study intends to collect lessons from the RNA-modified DC vaccine studies and previous preclinical studies to improve the response rate of DC-based vaccines in melanoma patients
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