Human allo-reactive CD4+ T cells as strong mediators of anti-tumor immunity in NOD/scid mice engrafted with human acute lymphoblastic leukemia

Abstract

Adoptive immunotherapy with donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (alloSCT) may not only mediate Graft-versus-Leukemia (GvL) reactivity, but also induce Graft-versus-Host Disease (GvHD). As HLA-class II molecules are predominantly expressed on hematopoietic cells, CD4 þ T cells may selectively mediate GvL reactivity without GvHD. Here, we assessed the capacity of human CD4 þ T cells to act as sole mediators of GvL reactivity in a NOD/scid mouse model for human acute lymphoblastic leukemia and chronic myeloid leukemia in lymphoid blast crisis. Highly purified CD4 þ DLI eradicated the leukemic cells. The anti-tumor immunity was mediated by a polyclonal CD4 þ T cell response comprising cytokine-producing T-helper and cytolytic T-effector cells directed against the mismatched HLA-class II molecules of the patients. Furthermore, primary leukemic cells acquired an antigen-presenting cell (APC) phenotype in vivo after DLI, as well as in vitro after co-culture with leukemia-specific CD4 þ T cells. In conclusion, our results show that CD4 þ T cells can be strong mediators of anti-tumor immunity, and provide evidence that cross-talk between CD4 þ T cells and leukemic cells is the basis for induction of leukemic cells with an APC phenotype. These data emphasize the clinical relevance of CD4 þ T cell based immunotherapy as treatment modality for hematological malignancies after alloSCT.

Rapid induction of single donor chimerism after double umbilical cord blood transplantation preceded by reduced intensity conditioning: results of the HOVON 106 phase II study

“…30,31 In addition to this, it was shown that alloreactive CD4 + T cells directed against mismatched HLA class II molecules were capable of directly eliminating leukemic cells in adult patients. 32 As many unit-recipient HLA class II mismatches were present, we hypothesize that HLA class II-specific CD4 + T cells of the ultimately surviving unit elicit an immediate and targeted alloreactive immune response towards mismatched HLA class II molecules of the nonengrafting unit in the absence of ATG. This hypothesis may be supported by the observation of a relatively rapid CD4 + T-cell recovery, by the abundance of class II mismatches, and also by the protracted presence of the nonengrafting unit in patients who had received a unit combination with a high inter-unit level of HLA matching.…”

HLA class II upregulation during viral infection leads to HLA-DP–directed graft-versus-host disease after CD4+ donor lymphocyte infusion

“…This is supported by our study demonstrating that leukemic cells can acquire a professional APC phenotype in vivo upon interaction and release of proinflammatory cytokines by allo-reactive CD41 T cells. 46 Moreover, we previously demonstrated that not only AML blasts, 47,48 but also other leukemic cells, 46-50 upregulated expression of HLA, adhesion, and costimulatory molecules in the presence of soluble factors and acquired an enhanced capacity to stimulate allogeneic T cells in vitro.…”

“…This is supported by our study demonstrating that leukemic cells can acquire a professional APC phenotype in vivo upon interaction and release of proinflammatory cytokines by allo-reactive CD41 T cells. 46 Moreover, we previously demonstrated that not only AML blasts, 47,48 but also other leukemic cells, 46-50 upregulated expression of HLA, adhesion, and costimulatory molecules in the presence of soluble factors and acquired an enhanced capacity to stimulate allogeneic T cells in vitro.In summary, we showed in 2 patients that prophylactic CD41 DLI administered early after HLA-DPB1-mismatched TCD-alloSCT led to conversion to donor hematopoiesis with concomitant GVHD caused by allo-reactive CD41 T cells directed against patientmismatched HLA-DPB1 alleles. Our results suggest that active CMV infection and subsequent expansion and cytokine release by residual patient-derived CMV-specific T cells may have provided essential inflammatory triggers for development of GVHD by HLA-DPB1-specific CD41 T cells.…”

Endogenous HLA class II epitopes that are immunogenic in vivo show distinct behavior toward HLA-DM and its natural inhibitor HLA-DO

“…[4][5][6][7] In a NOD/SCID mouse model for human acute lymphoblastic leukemia, infusion of human CD4 ϩ T cells led to eradication of the malignant cells. 8 Clinical trials in allogeneic stem cell transplantation (alloSCT) found that depletion of CD8 ϩ T cells from donor lymphocyte infusion preserved the ability of the T cells to induce conversion to donor chimerism, 9,10 highlighting the direct effector function of CD4 ϩ T cells.…”

“…[4][5][6][7] In a NOD/SCID mouse model for human acute lymphoblastic leukemia, infusion of human CD4 ϩ T cells led to eradication of the malignant cells. 8 Clinical trials in allogeneic stem cell transplantation (alloSCT) found that depletion of CD8 ϩ T cells from donor lymphocyte infusion preserved the ability of the T cells to induce conversion to donor chimerism, 9,10 highlighting the direct effector function of CD4 ϩ T cells.Antigen presentation to T cells by HLA surface molecules depends on protein degradation mediated by proteasomes and lysosomal proteases as the 2 major cellular breakdown mechanisms. Traditionally, it has been assumed that HLA class II molecules present exogenous antigens which are degraded by proteases within the endosomal/lysosomal system, whereas endogenous cytosolic antigens are degraded by the proteasome and presented by HLA class I molecules.…”