Abstract
Although melanoma is one of the most immunogenic tumors, it has an ability to evade anti-tumor immune responses by exploiting tolerance mechanisms, including negative immune checkpoint molecules. The most extensively studied checkpoints represent cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Immune checkpoint inhibitors (ICI), which were broadly applied for melanoma treatment in the past decade, can unleash anti-tumor immune responses and result in melanoma regression. Patients responding to the ICI treatment showed long-lasting remission or disease control status. However, a large group of patients failed to respond to this therapy, indicating the development of resistance mechanisms. Among them are intrinsic tumor properties, the dysfunction of effector cells, and the generation of immunosuppressive tumor microenvironment (TME). This review discusses achievements of ICI treatment in melanoma, reasons for its failure, and promising approaches for overcoming the resistance. These methods include combinations of different ICI with each other, strategies for neutralizing the immunosuppressive TME and combining ICI with other anti-cancer therapies such as radiation, oncolytic viral, or targeted therapy. New therapeutic approaches targeting other immune checkpoint molecules are also discussed.
Highlights
The concept of cancer immunosurveillance is based on the fact that tumor cells can be recognized and eliminated by immune system [1,2]
This tumor develops immune escape mechanisms that stimulate a fast melanoma progression. Such mechanisms include impaired antigen presentation by tumor cells, accumulation of dysfunctional effector T cells and generation of the immunosuppressive tumor microenvironment (TME) represented by Myeloid-Derived Suppressor Cells (MDSC), tumor associated neutrophils (TAN), Cancer-Associated Fibroblasts (CAF), Tumor-Associated Macrophages (TAM), and Treg
Approved immunotherapies with Immune checkpoint inhibitors (ICI) have revolutionized the treatment of melanoma. This treatment significantly increased the survival of melanoma patients and provided a durable control of the disease [26,27,28]
Summary
The concept of cancer immunosurveillance is based on the fact that tumor cells can be recognized and eliminated by immune system [1,2]. Immunogenicity of malignant melanoma is based on a high ultraviolet-driven mutational burden [3] This leads to the overexpression of tumor specific antigens enabling the formation of the antigen specific immune response [4,5]. Playing a pivotal role in the maintenance of self-tolerance under physiological conditions, these checkpoint molecules could be exploited by tumors to evade the immune responses. Inhibiting such interactions could reactivate anti-tumor immune reactions [14]. The combination of anti-CTLA-4 and anti-PD-1 antibodies was shown to work synergistically by expanding activated effector CD8 T cells [15,16]. This review will focus on current achievements in the therapy with immune checkpoint inhibitors (ICI) in melanoma and will discuss the strategies to improve of treatment efficacy by combining ICI with other therapies
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