Further supporting the notion of ongoing immune responses to tumors, antibodies that block inhibitory molecules on T cells induce long-term remission in a subset of cancer patients (7). killed by cytotoxic CD4+ T cells in a perforin/granzyme B-dependent manner. By contrast, MHCIINEG myeloma cells are killed by IFN- stimulated M1-like macrophages. In summary, while the priming phase of CD4+ T cells appears similar for MHCIIPOS and MHCIINEG tumors, the killing mechanisms are different. Unresolved issues and directions for future research are addressed. and injected back to lymphopenic patients, have a clinical effect in some patients (6). Further supporting the notion of ongoing immune responses to tumors, antibodies that block inhibitory molecules on T cells induce long-term remission in a subset of cancer patients (7). Finally, parameters that indicate immune activation in tumors are associated with improved prognosis (8). CD4+ versus CD8+ T Cells in Tumor Immunology Traditionally, CD8+ T cells have been thought to be the major mediators of effective anti-tumor T cell responses. Such a view is supported by the pronounced cytotoxic activity of CD8+ T cells cancer antigens; the tumor-specific myeloma protein V region idiotype (Id) (26, 27) and the melanoma-associated tyrosinase-related protein 1 (Trp1) (35). In other TCR-transgenic models, the antigens are either minor histocompatibility antigen Dby (H-Y) (28), viral antigens such as the hemagglutinin (HA) (40C42), or xenogeneic proteins such as ovalbumin (OVA) (17, 43, 44). While the transgenic TCR specific for the mutated myeloma antigen was obtained after immunization of mice syngeneic to the tumor (45, 46), the transgenic TCR specific for the non-mutated antigen was obtained after immunization of Trp1-deficient mice. Thus, in the latter model, Trp1 represents a foreign antigen to which high-affinity TCRs are induced (due to a lack of T cell tolerance) (35). Table 1 TCR-transgenic models employed in studies of anti-tumor CD4+ T cell responses. (68)toward MHC IIPOS targets, including tumor cells, have Hyperoside been described by several authors (37, 45, 70, 71). Correspondingly, efficient elimination of MHC IIPOS tumors by T cells with such properties is also observed (26, 28, 33, 35, 37, 38, 72). Several effector mechanisms have been implicated for tumor-specific cytotoxic CD4+ T cells. In a model of Id-specific CD4+ T cell responses against an MHC IIPOS B lymphoma, cytotoxicity was shown to TBLR1 be dependent on signaling mediated by binding of Fas ligand (FasL) on CD4+ T cells to Hyperoside the death receptor Fas on tumor cells (66). Na?ve T cells showed little killing activity, whereas Th1 differentiation greatly enhanced cytotoxicity. However, elimination of tumor cells was not affected in FasL-deficient ((66). Indeed, if the tumor antigen is secreted as is the case in the studies of Lundin et al. (33, 66), the indirect mechanism via Th1/M1 macrophages described below could also be active, and might play a prominent role in tumor rejection. In the Trp1-specific TCR-transgenic model, it was demonstrated that the rejection of B16 melanoma cells was abrogated in mice deficient for either granzyme B or perforin, indicating that these molecules are important for CD4+ T cell-mediated killing of MHC IIPOS tumor cells (37). In summary, different MHC IIPOS tumors may vary in susceptibility to various effector mechanisms of CD4+ T cells, as indicated by the observations addressed above. Indirect Killing of MHC Class IINEG Tumor Cells In general, antibody-secreting plasma cells are MHC class II negative due to silencing of the MHC Class II trans-activator (CIITA) occurring during plasma cell differentiation (73, 74). Multiple myeloma (MM) Hyperoside is the malignant counterpart of plasma cells and usually express little if any MHC class II molecules. MHC class II negativity due to.