For many years, visions for development of successful immunotherapy of cancer revolved around the induction of immune responses against tumor-specific ‘‘neoantigens.’’However, as demonstrated in a recent paper in the Proceedings by Overwijk et al.(1), the generation of tissue-specific autoimmune responses represents an approach to cancer immunotherapy that is gaining momentum. Thus, a new principle in cancer therapy states that the ability to induce tissue-specific autoimmunity will allow for the treatment of many important cancers. The original focus on tumor-specific neoantigens derived from a number of findings. Vaccination-challenge experiments performed between carcinogen-induced murine tumor models typically demonstrated that autologous tumors vaccinated much more effectively against themselves than against other independently derived tumors even of the same histologic type (2). These results were taken to imply that unique antigens specific to a particular tumor were more ‘‘immunogenic’’than shared antigens that would be expressed by multiple different tumors. This implication appeared to be corroborated when T cell clones raised against murine tumors were found to be specific exclusively for the tumor against which they were raised and failed to recognize other tumors derived from syngeneic animals (3). The revolution in cancer genetics provided an apparent molecular basis for these experimental findings. As it became clear that cancer was a disease characterized by genetic instability (4), the tremendous array of genetic alterations unique to each tumor could provide unique peptide sequences, which when presented on a tumor’s MHC molecules would represent tumor-specific neoantigens capable of being recognized by T cells. Such a view of the tumorspecific antigen was quite distinct from the majority of tumor antigens recognized by antibodies, which tended to recognize ubiquitously expressed cell-surface antigens whose structure was modified in tumors by posttranslational events, most commonly altered glycosylation (5). From the standpoint of immunotherapy, the concept of targeting unique tumor-specific antigens provided two fundamental advantages. First, immune responses targeted against unique antigens theoretically would be exquisitely tumorspecific and produce no collateral damage to normal cells. Second, it was imagined that immune tolerance to tumorspecific neoantigens might not be particularly stringent as these would have arisen subsequent to development of the mature adult immune system. Thus, tolerance to neoantigens could be broken or superceded more easily than tolerance to self-antigens. These potential advantages are balanced against a significant disadvantage, namely that immune therapies targeted against unique tumor-specific antigens would by necessity be individualized rather than generic, thereby dramatically increasing the cost and labor intensity of treating large numbers of patients.

Over the past 5 years, a set of surprising experimental findings from studies of human antitumor immune responses has led to a shift in emphasis from unique tumor-specific antigens to tissue-specific self-antigens as promising targets for immune therapy. This shift began in 1994 when Coulie and