Elsevier

Human Immunology

Volume 70, Issue 5, May 2009, Pages 331-339
Human Immunology

Melanoma vaccines: The problems of local immunosuppression

https://doi.org/10.1016/j.humimm.2009.01.017Get rights and content

Abstract

The incidence of cutaneous melanoma in Europe is rising, and the disease is incurable once metastases occur. Because melanoma expresses antigens that can be specifically recognized by the immune system, and because this disease occasionally undergoes spontaneous regression mediated by anti-tumor immunity, a number of different melanoma vaccines have been developed and tested clinically. Although most such vaccines show efficacy in vitro and an ability to stimulate anti-melanoma immune responses in blood, they have proved disappointing in clinical practice. It has become increasingly clear that the interaction between melanoma and the immune system is determined locally, within the tumor or draining lymph nodes. It is now clear that melanoma cells have the ability to anergize the immune system by inducing an immunosuppressive microenvironment that may explain the inability of systemic vaccines to alter patient outcomes. This subversion of the immune system involves alteration of dendritic cell (DC) function by tumor-derived cytokines, leading to the generation of suppressive and regulatory T lymphocytes. Successful melanoma vaccination probably requires therapeutic neutralization of the immunosuppressive microenvironment, which will require greater understanding of the molecular mechanisms used by the tumor to promote immunosuppression. Nevertheless, if these problems can be overcome, it seems likely that the efficacy of melanoma vaccines could be greatly enhanced.

Section snippets

How melanoma avoids immune recognition: Current theories

The complex interactions between the immune system and developing malignancies have been studied by many. The fact that immunogenic tumors such as melanoma develop in otherwise immunocompetent patients and the coexistence of tumor-specific immunity with a progressing tumor remain among the major paradoxes of tumor immunology [21], [22]. Among several theories that have been constructed to explain this paradox, those most commonly quoted are those of immune surveillance [23], recently updated to

Strategies for evoking anti-melanoma immune response

Activation of the immune response requires recognition of an immunogenic molecule, and if the memory response is to be generated, it is necessary that the antigen is presented in the context of HLA class II molecules by an APC to T lymphocytes, supported by co-stimulatory signals. To find suitable antigens for vaccine purposes, melanoma proteins have been screened for peptides with potent immunostimulatory characteristics, presented by both HLA class I and II, to activate both cytotoxic and

Melanoma vaccines—a lesson from uveal melanoma

Uveal melanoma is another aggressive malignancy originating from melanocytes. Because this tumor arises in an immunoprivileged site, it is interesting to analyze how this affects uveal melanoma immunogenicity and whether immunotherapy will be feasible.

Thanks to its privileged localization, uveal melanomas can safely express tumor-associated antigens [96], [97], and HLA class I molecules [98], to which the host is not tolerized [99]; hence it constitutes a potent stimulus for anti-melanoma

Melanoma vaccines–future possibilities

Although some mechanisms for interaction between a melanoma and the immune system have been discovered, including alteration of DC function and maturation by tumor-derived cytokines leading to the generation of suppressive and regulatory T lymphocytes, the exact molecular pathways need to be investigated. Investigations of the local and systemic immune suppression within melanoma will allow the dissection of discriminating immune system–related key events in melanoma progression, and generate

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