doi:10.1006/scbi.2001.0397, available online at http://www.idealibrary.com on seminars in CANCER BIOLOGY, Vol. 12, 2002: pp. 63–71 Strategies to overcome immune ignorance and tolerance Miguel-Angel Perales ∗ , Nathalie E. Blachere, Manuel E. Engelhorn, Cristina R. Ferrone, Jason S. Gold, Polly D. Gregor, Gabriele Noffz, Jedd D. Wolchok and Alan N. Houghton ∗ Cancer poses a difficult problem for immunotherapy because it arises from the host’s own tissues. Many of the target antigens are tissue-specific molecules shared by cancer cells and normal cells. Thus, these are weak antigens that do not typically elicit immunity. In addition, tumors have several features that make their recognition and destruction by the immune system difficult. Despite these obstacles, several strategies for developing effective tumor immunity have been developed. Crucial to these approaches is the discovery and understanding of the molecular identity of antigens and the mechanisms involved in tumor immunity. In this review, strategies to overcome immune ignorance and tolerance are discussed. Key words: cancer / differentiation antigen / melanoma / tolerance / tumor immunity c  2002 Academic Press What does the immune system see in cancers? The immune system has evolved to protect the host from microbial infections by distinguishing ‘self’ from ‘non-self’. Cancer, however, poses a difficult problem in that it arises from the host’s own tissues. Therefore, nearly all the genes expressed by tumors are also expressed by normal tissues. How does the immune system know to attack tumors or ‘altered self’ and spare normal tissues or ‘self’? Immune recognition of cancer has been well doc- umented in humans, and experimental systems have From the Memorial Sloan-Kettering Cancer Center and Weill Medical School and Graduate School of Cornell University, 1275 York Avenue, New York, NY 10021, USA. *Corresponding authors. E-mails: peralesm@mmskcc.org or a_houghton@ski.mskcc.org c  2002 Academic Press 1044–579X / 02 / 010063+ 09 / $35.00 / 0 shown that the immune system is capable of rejecting cancer. Furthermore, the immune system may have a role in protecting the host from developing tumors, known as immune surveillance, only allowing the pro- gression of microscopic foci that are able to evade the immune response. The paucity of antigens suitable for an immune response against cancer represents only one of the difficulties in developing viable immunotherapy for malignancies. It has become clear in the past several years that tumors have several features that make their recognition and destruction by the immune system difficult. Like pathogens, cancers may acquire mechanisms of immune evasion due to the evolutionary selection of clones that can survive in an immunocompetent host. Furthermore, cancers may develop additional strategies to avoid immune destruction due to pressures exerted by immunotherapy. Despite these difficulties, several strategies for de- veloping effective tumor immunity have come from our laboratory. In this review, we will discuss the strate- gies to overcome immune ignorance and tolerance, with special emphasis on work from our group. We will first describe the antigens seen by the immune sys- tem in cancer, then describe the difficulties in devel- oping an immune response to tumor antigens (TAs), and finally present strategies to overcome tolerance and ignorance to self-antigens. Tumor antigens (TA) (see Table 1) Mutations of genes or atypical gene products An accumulation of genetic mutations is thought to result in cancer. However, the immune system is not always able to detect genetic changes. Mutations can lead to increased immunogenicity of an epitope or changes in stability or trafficking. In the case of genes encoding p53, the p16/INK4a target CDK4, 63