engleski

SOLID TUMOR VACCINES ELICIT DISTINCT IMMUNE RESPONSES FROM HOST VERSUS DONOR T CELLS IN MIXED CHIMERAS CREATED BY NON-MYELOABLATIVE ALLOGENEIC STEM CELL TRANSPLANTATION (NST)

A growing body of evidence suggests that functional unresponsiveness of the immune system to growing solid tumors may be due to tolerance in tumor-specific CD4+ T cells, whereas tumor-specific CD8+ T cells exist in a state of partial activation with limited effector function. We therefore hypothesized that an allogeneic graft-versus-host reaction may provide a helper effect that augments the anti-tumor immune response of host CD8+ T cells in mixed hematopoietic chimeras. To test this hypothesis, we analyzed host versus donor T cell responses to AH1, an H-2Ldrestricted tumor antigen expressed by CT-26, a colon cancer of BALB/c mice. BALB/c mice with pre-established subcutaneous tumor underwent NST from MHC-compatible B10.D2 donors. Two weeks later, groups of chimeras received nothing, B10.D2 splenocytes IV, CT-26 tumor vaccine (irradiated CT-26 cells mixed with a GM-CSF secreting bystander cell line), or both. By staining with H-2Ld tetramers loaded with the AH1 423-431 a.a. peptide, AH1-speci.c CD8+ T cells were found to comprise 2-3% of total spleen CD8+ T cells three weeks after vaccination. In contrast, AH1-speci.c T cells could not be detected in the non-transplanted, tumor bearing mice. To further characterize AH1-specific T cells we characterized T cell avidity for antigen, as measured by binding of AH1 peptide-loaded, Ld IgG dimmers. AH1 specific T cells were easily expanded in vitro using AH-1 peptide pulsed irradiated BALB/c splenocytes. After four weeks of stimulation the highest percentages of cultures containing AH1-specific T cells were derived from tumor-bearing chimeras that received B10.D2 splenocytes and a CT-26 vaccine. Expanded cultures contained AH-1 specific CD8+ T cells derived from the host and the donor, based on the differential expression of Ly9.1 marker on the host lymphocytes and consistent with our recent observations in short-term cultures (Luznik, L. et al: Blood ; in press). Interestingly, AH1-specific allogeneic and host CD8+ T cells, expanded from the mixed chimeras had a higher affinity than the T cells derived from the vaccinated non-transplanted mice. In conclusion, mixed chimerism provides an optimal platform for immunotherapy of solid tumors not only because of allogeneic effect but also through augmentation of host tumor-specific immunity.

Tumor Vaccines; donor T cells; mixed chimeras

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