Recent Successes and Future Directions in Immunotherapy of Cutaneous Melanoma

Abstract

The global health burden associated with melanoma continues to increase while treatment options for metastatic melanoma are limited. Nevertheless, in the past decade, the field of cancer immunotherapy has witnessed remarkable advances for the treatment of a number of malignancies including metastatic melanoma. Although the earliest observations of an immunological antitumor response were made nearly a century ago, it was only in the past 30 years, that immunotherapy emerged as a viable therapeutic option, in particular for cutaneous melanoma. As such, melanoma remains the focus of various preclinical and clinical studies to understand the immunobiology of cancer and to test various tumor immunotherapies. Here, we review key recent developments in the field of immune-mediated therapy of melanoma. Our primary focus is on therapies that have received regulatory approval. Thus, a brief overview of the pathophysiology of melanoma is provided. The purported functions of various tumor-infiltrating immune cell subsets are described, in particular the recently described roles of intratumoral dendritic cells. The section on immunotherapies focuses on strategies that have proved to be the most clinically successful such as immune checkpoint blockade. Prospects for novel therapeutics and the potential for combinatorial approaches are delineated. Finally, we briefly discuss nanotechnology-based platforms which can in theory, activate multiple arms of immune system to fight cancer. The promising advances in the field of immunotherapy signal the dawn of a new era in cancer treatment and warrant further investigation to understand the opportunities and barriers for future progress.

Keywords: adoptive T cell transfer; immune checkpoint blockade; immunotherapy; melanoma; programmed cell death protein 1; tumor microenvironment; tumor-infiltrating dendritic cell; tumor-infiltrating lymphocyte.

Figure 1

Clinical and histological presentation of melanoma. (A) Superficial spreading melanoma (SSM), (B) nodular melanoma (NM), (C) acrolentiginous melanoma (ALM), (D) H&E stain of NM depicting asymmetrical nodular tumor infiltrates in the upper dermis. Nests of atypical cells are visible in the dermis and at the dermoepidermal junction. (E) Immunohistochemical staining for Melan-A reveals red stained atypical tumor cells in the dermis and epidermis (Images courtesy of RH).

Figure 2

Schematic of the roles dendritic cells (DC) play in antitumor immune response. DC take up and process tumor-associated/tumor-specific antigens (TAA/TSA) from dying tumor cells, undergo maturation, and migrate to tumor draining lymph nodes (LN) where they can present antigen to lymphocytes. Tumor-specific T cells then egress from the LN and infiltrate the tumor. Effector CD8+ cytotoxic T lymphocytes play a major role in killing tumor cells, leading to further release of TAA/TSA for DC uptake and subsequent presentation. Inset panel: Costimulatory and inhibitory interactions at the antigen-presenting cell (APC)–T cell immunological synapse. The activation of T cells by APC is tightly regulated by multiple ligand–receptor interactions. TCR binds to cognate antigen (AG) in the context of their specific MHC. Costimulatory molecules such as CD80 (B7.1) and CD86 (B7.2) on APC can either bind to CD28 on T cells resulting in downstream activation of T cell effector genes or to cytotoxic T lymphocyte antigen-4 (CTLA-4) resulting in inhibition. Further T cell activation is achieved through cytokines. Programmed cell death protein 1 (PD-1) is another immune checkpoint receptor and is expressed on activated T cells. The primary ligand for PD-1 (PD-L1) is expressed on APC and on some tumor cells, and upon binding to PD-1 acts to inhibit T cell activation.

Figure 3

Multifunctional nanoparticles (NP) in cancer treatment. NP can be tailored to specific applications in tumor immunotherapy using versatile designs of various sizes, constituent biomaterials, and surface modifications. The surface of NP can be functionalized with specific polymers and antibodies to increase their targeting to certain types of cells. Liposomes are self-assembling nanosized vesicles comprised of phospholipids and cholesterol arranged in one or more lipid bilayers enclosing an aqueous core. NP such as liposomes can be used as platforms for the simultaneous delivery of multiple agents, such as (A) immunotherapeutics, e.g., anti-PD-L1 and anti-cytotoxic T lymphocyte antigen-4 (CTLA-4), to enhance the function of tumor-specific effector T cells; (B) tumor-associated antigens (TAA) and adjuvant targeted to dendritic cells (DC) to promote their function; (C) chemotherapeutics and targeted release thereof, for instance, using thermosensitive NP, to promote cancer cell death.