Dendritic cells (DCs) that acquired antigen from apoptotic tumor cells are able to induce major histocompatibility complex (MHC) class I-restricted cytotoxic T lymphocytes and antitumor immunity. In the present study, we investigated the efficiency of antitumor immunity derived from DCs that had phagocytosed apoptotic/necrotic BL6-10 melanoma cells compared with that of DCs pulsed with the tumor mTRP2 peptide. Our data showed that phagocytosis of apoptotic/ necrotic tumor cells resulted in maturation of DCs with up-regulated expression of proinflammatory cytokines [interleukin (IL)-1␤, IL-6, tumor necrosis factor-␣, interferon-␥ and granulocyte-macrophage colony-stimulating factor], chemokines (MIP-1␣, MIP-1␤ and MIP-2), the CC chemokine receptor CCR7 and the cell surface molecules (MHC class II, CD11b, CD40 and CD86), and down-regulated expression of the CC chemokine receptors CCR2 and CCR5. These mature DCs displayed enhanced migration toward the CC chemokine MIP-3␤ in a chemotaxis assay in vitro and to the regional lymph nodes in an animal model in vivo. Our data also showed that vaccination with DCs that had phagocytosed apoptotic/necrotic BL6-10 cells was able to (i) more strongly stimulate allogeneic T-cell proliferation in vitro, (ii) induce an in vivo Th1-type immune response leading to more efficient tumor-specific cytotoxic CD8 ؉ T-cell-mediated immunity and (iii) eradicate lung metastases in all 6 vaccinated mice compared with mice vaccinated with DCs pulsed with the tumor mTRP2 peptide, in which lung metastases were reduced (mean number of 16 per mouse) but not completely eradicated. Therefore, DCs that had phagocytosed apoptotic/necrotic tumor cells appear to offer new strategies in DC cancer vaccines. © 2001 Wiley-Liss, Inc. Key words: cancer vaccine; dendritic cell maturation; apoptotic/ necrotic tumor cellCytotoxic T lymphocytes (CTLs) play a major role in the rejection of immunogenic tumors. 1 Classically, CTLs target tumors through recognition of a ligand consisting of the self major histocompatibility complex (MHC) class I molecule and peptides that are generally derived from tumor antigens synthesized within the tumor cells. 2,3 However, there is evidence for an exogenous pathway whereby antigens that are not expected to gain access to the cytoplasm are presented on MHC class I molecules. 4 -6 A most striking example of this is the in vivo phenomenon of crosspriming: antigens from donor cells are acquired by host antigenpresenting cells (APCs) and presented on MHC class I molecules in the appropriate context of co-stimulation. Delivery of exogenous antigen to the endogenous MHC class I-restricted processing pathway of APCs is a critical challenge in cancer vaccine design.Dendritic cells (DCs) are one of the most potent APCs. They capture antigens in situ, and migrate to lymphoid organs to interact/activate naive T cells. 7 DCs pulsed with synthetic tumorderived MHC class I-restricted peptides or tumor lysates and tumor cell-derived RNA induced significant CTL-dependent antitumor immune respon...

Although both Bcl-2/Bax ratio and Mcl-1 have been identified to be of clinical relevance in B-cell chronic lymphocytic leukemia (CLL), there is controversy regarding their role; further, their relative importance is not well delineated. Expression of Bcl-2, Bax, the Bcl-2/Bax ratio, and Mcl-1 in 51 consecutive previously untreated CLL patients and 16 controls was determined by Western blotting. Only 37 patients were treated, all with chlorambucil and prednisone initially. Six patients achieved complete response (CR), 14 were non-responders (NR), and 17 had a partial response (PR), as defined by NCI criteria. There was considerable inter-patient variability in protein expression and overlap with healthy volunteers (P > 0.05). All patients with CR had low Mcl-1 levels compared to the PR + NR group (0.07 ± 0.02 vs. 0.14 ± 0.07, P = 0.043). Higher Mcl-1 expression as determined by dichotomizing the data was associated with a failure to achieve CR (P = 0.021). The Bcl-2/Bax ratio was significantly associated with treatment response only when CR and PR were considered together (0.89 ± 0.53 [CR + PR] vs. 3.38 ± 4.47 [NR], P = 0.0118). There was no association with Rai stage. Low Mcl-1 appears to be a requirement for CR, while low Bcl-2/Bax ratio is indicative of some response to conventional treatment. Am.

No abstract