Immunity to Cancer Through Immune Recognition of Altered Self: Studies with Melanoma

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Abstract

The adaptive immune system is capable of recognizing cancer through T- and B-cell receptors. However, priming adaptive immunity against self antigens is potentially a difficult task. Presentation of altered self to the immune system is a strategy to elicit immunity against poorly immunogenic antigens. We have shown that immunization with conserved paralogues of tumor antigens can induce adaptive immunity against self antigens expressed by cancer. Remarkably, cancer immunity elicited by closely related paralogues can generate distinct adaptive immune responses, either antibody or T-cell dependent. Cancer immunity induced by xenogeneic immunization follows multiple and alternative pathways. The effector phase of tumor immunity can be mediated by cytotoxic T cells or macrophages and perhaps natural killer cells for antibody-dependent immunity. Helper CD4+ T cells are typically, but not always, required to generate immunity. Autoimmunity is frequently observed following immunization. Cancer immunity and autoimmunity use overlapping mechanisms, and therefore they are difficult to uncouple, but distinct pathways can be discerned that open the eventual possibility of uncoupling tumor immunity from autoimmunity. Studies examining the molecular basis for immunogenicity of conserved paralogues are facilitating the development of new strategies to rationally design vaccines that trigger adaptive immune responses to cancer.

Introduction

Melanoma is a malignant tumor arising from melanocytes in epithelium. This malignancy metastasizes readily and responds poorly to any form of therapy once it has metastasized. Melanoma is the most deadly form of skin cancer, and in the year 2000, almost 50,000 cases of malignant melanoma were predicted to occur in the United States in 2003. The risk of melanoma increases with age, but it frequently affects young, otherwise healthy people and represents the number one cause of cancer death in women aged 20–30 years (Agarwala and Kirkwood, 2002). The identification of an effective therapy against melanoma still represents a major endeavor. In this review, we have compiled some of the most relevant findings that may help us understand immune responses against melanoma antigens, and we discuss new immunotherapeutic strategies against melanoma.

Cancer vaccine development faces the fundamental difficulty that cancer cells arise from the host's self tissues. Because most tumor antigens are products of normal or altered cellular genes, they are typically not efficient at initiating an immune response. Thus, a crucial problem in cancer immunotherapy is how to efficiently prime immune cells to respond to poorly immunogenic tumor antigens. Immune recognition and rejection of cancer cells have been extensively documented in experimental models, and immune recognition of cancer antigens has been characterized in healthy humans and individuals with cancer. Recent experiments in mouse models have resurrected the notion of immune surveillance, with immunological pressures shaping and editing tumors. In immune surveillance, incipient de novo malignancies are attacked by innate and adaptive immune responses, but immune editing selects cancer cell populations with the ability to evade and survive the recognition by the immune system.

Despite these obstacles, approaches for triggering effective tumor immunity have been developed. Essential to the success of these strategies has been the detailed understanding of the biological mechanism involved in tumor immunity. We briefly describe the types of melanoma antigens seen by the immune system, characterize the mechanism underlying tumor immunity and autoimmunity, and finally describe our current clinical strategies in the area of active immune therapy.

Section snippets

Germ Cell-Cancer Antigens

These antigens are normally present in male germ cells, which lack major histocompatibility complex (MHC) surface expression and are also expressed by certain tumors (these antigens are also called cancer-testes antigens or tumor-specific shared antigens). Although germ cell antigens are silenced in healthy somatic cells, they are reexpressed in certain malignancies, probably through changes in DNA methylation. Among these antigens, MAGE-1 was identified as the first human gene product on

Cellular Immune Responses

The protective immune response against tumors and invading intracellular pathogens relies in part on the vigorous attack of cytotoxic T lymphocytes (CTLs). This response occurs on recognition by the T-cell receptor (TCR) of short peptides (8–10 amino acids) bound to self MHC class I molecules on the surface of target cells. These short peptides are the products of proteolytic processing of tumor or pathogen-derived proteins. On primary immunization, naive CD8+ T cells proliferate in the

Antibody-Mediated Immunity in Melanoma

Experiments with the melanoma differentiation antigen gp75 are an ideal platform for exploring the mechanism of humoral immunity, because antibodies to gp75 induce both tumor rejection and autoimmunity. The 80% homologous human and mouse gp75 proteins are recognized by the mouse IgG2a monoclonal antibody TA99 (Vijayasaradhi 1991, Vijayasaradhi 1991). Cellular localization of gp75 is mainly melanosomal, but ∼2% of the newly synthesized protein resides on the cell surface, where it is accessible

Heteroclitic Peptides

For many decades, various strategies for cancer immunization have been proposed and tested in clinical trials. Although many studies have immunized patients with dead or attenuated tumor cells (Berd 1991, Bystryn 1992), this method does not allow an accurate quantification of the immune response to specific antigens. Peptide vaccines have more recently been used to immunize patients with melanomas against specified epitopes on tumor cells (Brichard et al., 1993). An important discovery, which

Acknowledgements

The authors wish to thank Swim Across America, Mr. William H. Goodwin, Mrs. Alice Goodwin, and the Commonwealth Cancer Foundation for Research and Experimental Therapeutics Cancer Center of MSKCC, the Quentin J. Kennedy Family Foundation, T. J. Martell Foundation, and grants from the National Cancer Institute. M. J. T. was also supported by the Sloan-Kettering Institute “Immunology Tanining Grant” and J. D. W. by the New York City Council Speaker's Fund for Biomedical Research and the Etta

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