OMIC signatures to understand cancer immunosurveillance and immunoediting: Melanoma and immune cells interplay in immunotherapy

Abstract

Melanoma is the deadliest form of skin cancer. Cutaneous melanomas usually originate from exposure to the mutagenic effects of ultraviolet radiation, and as such they exhibit the highest rate of somatic mutations than any other human cancer, and an extensive expression of neoantigens concurrently with a dense infiltrate of immune cells. The coexistence of high immunogenicity and high immune cell infiltration may sound contradictory for cancers carrying a gloomy outcome. However, recent studies have unveiled a variety of immunosuppressive mechanisms that often permeate the tumor microenvironment and that are responsible for tumor escaping from immunosurveillance mechanisms. Nonetheless, this particular immune profile has opened a new window of treatments based on immunotherapy that have significantly improved the clinical outcome of melanoma patients. Still, positive and complete therapy responses have been limited, and this particular cancer continues to be a major clinical challenge. The transcriptomic signatures of those patients with clinical benefit and those with progressive disease have provided a more complete picture of the universe of interactions between the tumor and the immune system. In this review, we integrate the results of the immunotherapy clinical trials to discuss a novel understanding of the mechanisms guiding cancer immunosurveillance and immunoediting. A clear notion of the cellular and molecular processes shaping how the immune system and the tumor are continuously coevolving would result in the rational design of combinatory therapies aiming to counteract the signaling pathways and cellular processes responsible for immunoescape mechanisms and provide clinical benefit to immunotherapy nonresponsive patients.

Significance of Tumor Mutation Burden in Immune Infiltration and Prognosis in Cutaneous Melanoma

“…Melanoma is one of the most aggressive forms of skin cancer, it accounts for only 5% of all skin cancer cases, but 80% of all skin cancer deaths (44). The occurrence, development, and evolution of melanoma are based on the accumulation of genomic changes, including high ultraviolet-driven mutation burdens, which makes melanoma the most immunogenic tumor (45,46).…”

The Complex Role of Autophagy in Melanoma Evolution: New Perspectives From Mouse Models

“…As many other cancer types, melanoma can provoke an intricate and multifaceted immune response which can be more or less deleterious for the tumor, depending on several factors (86,87). The involvement of autophagy in this context can very much depend on where it is exerting a major function in regulating the immune response and which immune cells are sensing and then responding to the different levels of autophagy (88)(89)(90)(91). For instance, the group of Verginis demonstrated that autophagy inhibition in myeloid-derived suppressor cells (MDSCs), a population of immune cells accumulating within the tumors with the function of suppressing the immune response (92), can redirect these cells toward an antitumor immune reaction (93).…”

Induction of Progenitor Exhausted Tissue-Resident Memory CD8+ T Cells Upon Salmonella Typhi Porins Adjuvant Immunization Correlates With Melanoma Control and Anti-PD-1 Immunotherapy Cooperation

“…It is interesting how these progenitor exhausted T cells converge as an important population for cancer control in both immunization and immunotherapy strategies. Understanding how these T cell populations are formed and modulated will be decisive for strategies of cooperative therapies, particularly because of the high number of patients with tumors refractory to immunotherapy or that relapse after an initial positive response (3,60,61).…”

“…The tumors width and length were measured using a caliper every 2 days starting at day 7. The tumor volume was calculated as 4/3p (1/2 width) 2 (1/2 length), in mm 3 . Tumor appearance was scored daily through manual palpation, and mice with no evidence of tumor by the end of the following period were scored as tumor-free.…”