The recognition that tumors could after all be suffiin the annals of contemporary cancer immunotherapy. ciently “foreign” to be recognized by the immune system There are three good reasons why tumor antigens has reinvigorated the efforts to identify and isolate tumor recognized by CTL would make effective tumor rejection antigens (Boon and van der Bruggen, 1996; Rosenberg, antigens.(1) The major histocompatibility complex 1999). This review will focus on what makes a tumor (MHC) class I processing pathway ensures that CTL are antigen a good or not-so-good target for immunoable to recognize subtle changes in the repertoire of therapy. antigens expressed by most (MHC class I–expressing) somatic cells (Townsend and Bodmer, 1989).(2) Murine Which Tumor Antigens Function as (Better) Tumor studies using antibody depletion or adoptive transfer of Rejection Antigens T cell subsets have shown that the CD8+ CTL arm of Tumor antigens can be classified according to the type the immune response, alone or sometime in combinaof immune response they elicit: humoral, cellular, CD4+ tion with CD4+ T cells, constitutes the primary antitumor (T helper), or CD8+ cytotoxic T lymphocyte (CTL) re- effector arm of the adaptive immune response.(3) Persponses. As will be discussed below, the fact that a haps the most compelling evidence stems from the fretumor antigen elicits a tumor-specific immune response quent correlation seen between tumor progression and does not necessarily mean that the immune response loss of histocompatibility leukocyte antigen (HLA) class will cause the rejection of the tumor in vivo. Thus, from I expression in cancer patients (Garrido et al., 1997; a vaccination standpoint, the question is which tumor Hicklin et al., 1999), strongly suggesting that progressing antigen can or is better at inducing a clinically beneficial tumors in cancer patients must have elaborate means of escaping an apparently effective MHC class I–restricted response. We refer to such antigens as “tumor rejection immune response. It is, however, becoming clear that antigens.” Tumor-rejection antigen is therefore an operthe CD4+ T cell response also plays an essential role ational term describing how well an immune response in tumor rejection. The primary role of CD4+ T cells, elicited against a tumor antigen will impact on tumor specifically, the Th-1 subset, is to enhance the induction growth. Tumor antigens can be poor, intermediate, or and/or extend the persistence of CD8+ CTL in vivo (Frasca et al., 1998; Zajac et al., 1998; Toes et al., 1999). CD4+ T cells have also been ascribed a direct effector