Immunotherapy for melanoma: current status and perspectives

Abstract

Immunotherapy is an important modality in the therapy of patients with malignant melanoma. As our knowledge about this disease continues to expand, so does the immunotherapeutic armamentarium. Nevertheless, successful preclinical models do not always translate into clinically meaningful results. The authors give a comprehensive analysis of most recent advances in the immune anti-melanoma therapy, including interleukins, interferons, other cytokines, adoptive immunotherapy, biochemotherapy, as well as the use of different vaccines. We also present the fundamental concepts behind various immune enhancement strategies, passive immunotherapy, as well as the use of immune adjuvants. This review brings into discussion the results of newer and older clinical trials, as well as potential limitations and drawbacks seen with the utilization of various immune therapies in malignant melanoma. Development of novel therapeutic approaches, along with optimization of existing therapies, continues to hold a great promise in the field of melanoma therapy research. Use of anti-CTLA4 and anti-PD1 antibodies, realization of the importance of co-stimulatory signals, which translated into the use of agonist CD40 monoclonal antibodies, as well as activation of innate immunity through enhanced expression of co-stimulatory molecules on the surface of dendritic cells by TLR agonists are only a few items on the list of recent advances in the treatment of melanoma. The need to engineer better immune interactions and to boost positive feedback loops appear crucial for the future of melanoma therapy, which ultimately resides in our understanding of the complexity of immune responses in this disease.

FIGURE 1

Role of Dendritic Cells (DCs) and Mechanisms of Tumor-Mediated Immunosuppression (schematic). The activation of immature dendritic cells (iDCs) is followed by migration to lymphatic nodes, sites of transformation to mature dendritic cells. The uptake and processing of antigens by DCs is the first step in the activation of T-effectors, NK-cells, CD4⁺-cells, and B-cells. Two different pathways involve the processing of endogenous (intracellular) and exogenous antigens (apoptotic cancer cells). Activation of cytotoxic T cells involve antigen cross-presentation of tumor antigens by DCs. DCs migration to lymph nodes (LNs) occurs through a CCR7 gradient. Subsequently, DCs complete the maturation process by expressing surface MHC-antigen complexes. Mature DCs are able to induce various cellular effectors against cancer cells, such as CD4⁺ (MHC II-restricted) and cytotoxic CD8⁺-cells (MHC I-restricted). Activation of NKT cells is made through a MHC-I restricted interaction between the Va24 T-cell receptor chain with the glycolipid α-GalCer, resulting in tumor cell killing. Other consequences of NKT-cell activation consist of CD8⁺-cell and NK cell stimulation, with consequent anti-tumor effects. Immune activation is however interfered by the inducement of immune tolerance by the tumor, or by the immature dendritic cells (DC) which lack proper antigenic stimulation. T-regulatory cells can interfere with DC-effector T-cell interactions and inhibit the DC activation, with resultant immune anergy. Tregs are activated by tumor-associated macrophages (TAMs) and interfere with the process of DC polarization. One immunosuppressive effect exerted by the T regs is mediated through CTLA4 receptor interaction with the B7 (CD80/CD86) ligands on the surface of T cells and DCs. Several other molecules (suppression of cytokine-signaling1, PD1) mediate tumor-induced immunosuppresson. TAM can produce an incomplete polarization of iDCs through various soluble facrors.