Cancer immunology

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

review article
Molecular Origins of Cancer

Cancer Immunology
Olivera J. Finn, Ph.D.

From the University of Pittsburgh School of Medicine, Pittsburgh. Address reprint requests to Dr. Finn at the Department of Immunology, University of Pittsburgh School of Medicine, E1044, Biomedical Science Tower, Pittsburgh, PA 15261, or atojfinn@pitt.edu. N Engl J Med 2008;358:2704-15.
Copyright © 2008 Massachusetts Medical Society.

M

ajor conceptual and technical advances in immunology over the past 25 years have led to a new understanding of cellular and molecular interplays between the immune system and a tumor. This review deals with important new concepts in antitumor immunity and their application to immunotherapy.T umor A n t igens
Identification

The immune system can respond to cancer cells in two ways: by reacting against tumor-specific antigens (molecules that are unique to cancer cells) or against tumor-associated antigens (molecules that are expressed differently by cancer cells and normal cells).1 Immunity to carcinogen-induced tumors in mice is directed against the products of unique mutationsof normal cellular genes. These mutant proteins are tumor-specific antigens.2 Tumors caused by viruses display viral antigens that serve as tumor antigens. Examples are the products of the E6 and E7 genes of the human papillomavirus, the causative agent of cervical carcinoma,3 and EBNA-1, the Epstein–Barr virus nuclear antigen expressed by Burkitt’s lymphoma and nasopharyngeal-carcinoma cells.4Whether tumors of unknown cause — which account for most human tumors — express antigens that the immune system can recognize remained in doubt until the development of methods for detecting and isolating them. The advent of hybridoma technology5 led to the development of monoclonal antibodies from mice that were immunized with human tumors. Monoclonal antibodies that reacted specifically with tumorcells were then used to characterize putative human tumor antigens.6 Nevertheless, there were doubts that the tumor-specific antigens that mouse monoclonal antibodies could detect would be recognized by the human immune system. The development of methods to propagate human T cells,7 and in particular tumor-specific T cells from patients with cancer, led to an important breakthrough: theidentification of MAGE-1, a melanoma-specific antigen that stimulates human T cells in vitro. With antigen-specific T cells as a reagent, it was possible to clone the MAGE-1 gene.8 The MAGE-1 studies showed that the human immune system can respond to tumor antigens, and the findings stimulated a productive effort to discover tumor antigens. The result is a long and still-growing list of antigens from avariety of tumors that could serve as targets for treatment.1,9 The proteasomes of normal and neoplastic cells break down proteins into short peptides, and major-histocompatibility-complex (MHC) class I molecules on antigenpresenting cells present these peptides to cytotoxic CD8 T cells. Peptides derived from products of mutated genes or abnormally expressed cancer-cell proteins can also be presentedto T cells (Fig. 1).10 Peptides bound to MHC class I or MHC class II
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n engl j med 358;25

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june 19, 2008

The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF LIVERPOOL on March 31, 2011. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved.

molecular origins of cancermolecules of tumors have been sequenced in a search for tumor-specific antigens.11-13 The ability to propagate dendritic cells14 made it possible to reconstitute an immune response in vitro. Dendritic cells could be loaded with various tumorderived peptides, proteins, or even whole tumor cells and cultured with T cells, mimicking what occurs in vivo (Fig. 2). Peptides of interest were...