Interaction of molecular alterations with immune response in melanoma

Abstract

Major advances have been made in melanoma treatment with the use of molecularly targeted therapies and immunotherapies, and numerous regimens are now approved by the US Food and Drug Administration for patients with stage IV disease. However, therapeutic resistance remains an issue to both classes of agents, and reliable biomarkers of therapeutic response and resistance are lacking. Mechanistic insights are being gained through preclinical studies and translational research, offering potential strategies to enhance responses and survival in treated patients. A comprehensive understanding of the immune effects of common mutations at play in melanoma is critical, as is an appreciation of the molecular mechanisms contributing to therapeutic resistance to immunotherapy. These mechanisms and the interplay between them are discussed herein. Cancer 2017;123:2130-42. © 2017 American Cancer Society.

Keywords: B-Raf proto-oncogene serine/threonine kinase (BRAF); catenin-β 1 (CTNNB1); combination therapy; guanosine-triphosphate guanyltransferase (GTPase); immunotherapy; melanoma; neoantigen; neuroblastoma rat sarcoma viral oncogene homolog (NRAS); personalized medicine; phosphatase and tensin homolog (PTEN); targeted therapy.

Figure 1. Immune effects of molecular alterations within the tumor microenvironment

Description of immune effects of BRAF^V600E, PTEN, β-Catenin and passenger mutations resulting in neoantigens on the immune tumor microenvironment. BRAF^V600E mutations have been proven to upregulate immunosuppressive cytokines VEGF, IL-1, 6, 10 and downregulate immunogenic melanoma antigens. PTEN loss has been shown to increase expression of VEGF, IL6, 10 and CCL2, leading to reduced T cell infiltration and poor response to checkpoint blockade. Aberrant β-Catenin activity leads to increased expression of IL-10, reducing the ability of DCs to mediate an anti-tumor T cell response. Increases in mutational load and neoantigens result in a potential increase in the antigenicity of the tumor.

Figure 2. Adaptive clinical trial design allows improved therapeutic decisions

A) Current approaches investigate limited molecular biomarkers prior to initiation of a standard therapy in a heterogeneous patient population, with little personalization. This results in modest and variable responses. B) An increasing number of trials now allows for adaptive decision making. These trials include more extensive molecular and immune profiling prior to a personalized medicine approach. Then, following treatment initiation, an early on-treatment biopsy is obtained for molecular and immune profiling in order to evaluate the success of the current therapy. As a result of this profiling, patients are either continued on this therapy, or switched to an alternate treatment regimen, enhancing responses to therapy.

Figure 3. Translational studies provide an optimal approach to understanding mechanisms and accelerating patient benefit

Much success has come from approaches investigating longitudinal patient samples from clinical trials. These samples are then used to formulated hypotheses and develop appropriate animal models where therapeutic mechanisms of response and resistance can be investigated and better understood in order to improve patient outcomes.