Concurrent Allorecognition Has a Limited Impact on Posttransplant Vaccination

Abstract

Transplantation of allogeneic hematopoietic stem cells with or without immunocompetent lymphocytes has proved a successful strategy in the treatment of hematological malignancies. We have recently shown that this approach can also cure mouse prostate cancer, provided that it is combined with tumor-specific vaccination. Whether the response to alloantigens acts by providing helper function to enhance vaccine-specific responses or in other ways impinges on vaccine immunogenicity remains to be clarified, and this question is of clinical relevance. In this study, we have addressed this issue by comparing the immunogenicity of dendritic cells pulsed with a peptide derived from a tumor/viral model Ag in recipients of donor cells either syngeneic to the host or differing for either Y-encoded or multiple minor H antigens. We report that vaccination elicits comparable proliferation and differentiation of peptide-specific CD8+ T cells despite concurrent expansion and differentiation of minor H antigen-specific IFN-γ effector T cells. Depletion of alloreactive CD4+ T cells reduced alloreactivity but not vaccine-induced CD8+ T cell priming, suggesting that alloresponses do not provide helper functions in peripheral lymphoid tissues. Vaccine-mediated T cell priming was also preserved in the case of multiple minor H antigen disparities, prone to graft-versus-host disease. Thus, in the context of nonmyeloablative allotransplantation aimed at restoring an effective tumor-specific T cell repertoire, minor H antigen-specific T cells do not interfere with vaccine-induced T cell priming, supporting the notion that posttransplant vaccination is a valuable strategy to boost tumor and pathogen-specific protective immunity.

Vaccine-Instructed Intratumoral IFN-γ Enables Regression of Autochthonous Mouse Prostate Cancer in Allogeneic T-Cell Transplantation

“…Of note, TRAMP recipients of male and female DLI responded equally well to the dendritic cell vaccine. This supports the notion that Tag-IV-specific T-cell priming was not influenced by concurrent alloreactivity, as we previously showed to be the case under tumor-free condition (25). Vaccine-induced T-cell responses in secondary lymphoid organs correlated with the onset of intratumoral proinflammatory responses.…”

“…Results depicted in Fig. 3 indicate that tumor-specific CTL accumulate to similar extents in the spleens of mDLI and fDLI TRAMP recipients, supporting the notion that alloreactive T cells do not contribute to Tagspecific T-cell priming (25). Analysis of UGA sections revealed the number of tumor-infiltrating CD3 þ cells, including both CD4 þ and CD8 þ T cells ( Supplementary Fig.…”

“…Having found that vaccine-induced T-cell priming and GVT responses can be observed over the course of GVHD (ref. 25 and Manzo, in preparation), several strategies might be envisaged to favor minor H antigen T-cell function/persistence. For instance, in vitro cancerres.aacrjournals.org Downloaded from strategies able to sensitize donor cells to host minor H antigen might be well worth considering.…”

Graft-versus-Host Disease Impairs Vaccine Responses through Decreased CD4+ and CD8+ T Cell Proliferation and Increased Perforin-Mediated CD8+ T Cell Apoptosis

“…Vaccines have demonstrated efficacy in the autologous setting in expanding T cells specific for tumor-associated antigens (TAA) and have the potential to enhance the graft-versus-leukemia (GVL) effect(11-18). We have previously demonstrated that even mild GVHD adversely impacts the magnitude of immune responses to a vaccine targeting antigens not expressed on normal host tissues(12) through an undefined mechanism.…”

“…We have previously demonstrated that even mild GVHD adversely impacts the magnitude of immune responses to a vaccine targeting antigens not expressed on normal host tissues(12) through an undefined mechanism. Although the deleterious impact of GVHD on T cell populations as a whole has been well established, few studies have carefully characterized the effect of the alloreactive environment on non-alloreactive T cells responding to a vaccine(18, 19). In this report, we studied the capacity for vaccine-responding T cells with known antigen specificity toward non-allogeneic antigens to proliferate and survive in the setting of GVHD after MHC-matched, mHA-mismatched alloBMT.…”