Antitumour activity mediated by CD4⁺ cytotoxic T lymphocytes against MHC class II‐negative mouse hepatocellular carcinoma induced by dendritic cell vaccine and interleukin‐12

Abstract

Summary When BALA/c mice with BNL hepatocellular carcinoma (HCC) were treated with dendritic cells fused with BNL cells (DC/BNL) and recombinant murine interleukin (IL)‐12, tumour development was significantly suppressed, whereas treatment with either DC/BNL or IL‐12 alone did not show a tumour‐suppressive effect. Antitumour activity induced by DC/BNL + IL‐12 was abrogated by depletion of CD4+ T cells, but not by depletion of CD8+ T cells or natural killer cells. Splenic CD4+ T cells and CD8+ T cells from DC/BNL‐treated mice showed cytotoxic activity against BNL cells after 3 days of incubation with DC/BNL, although BNL cells do not express major histocompatibility complex (MHC) class II molecules even after treatment with interferon (INF)‐γ. Furthermore, CD4+ T cells killed syngeneic‐irrelevant CT26 cells and even allogeneic Hepa1‐6 cells. This cytotoxicity was blocked by concanamycin A, but not by an anti‐Fas ligand (FasL) monoclonal antibody, indicating that cytotoxic activity was mediated by perforin. Immunofluorescence microscopy demonstrated that abundant CD4+ T cells and MHC class II‐positive macrophages, but not CD8+ T cells, had infiltrated tumour tissue in mice treated with DC/BNL + IL‐12. Flow cytometric analysis of tumour‐infiltrating cells in mice treated with DC/BNL + IL‐12 showed increases in CD4+ T cells and MHC class II+ CD11b+ cells but not in CD8+ T cells or MHC class I+ CD11b+ cells. Our results suggest that, in BNL‐bearing mice treated with DC/BNL + IL‐12, tumour macrophages activated by INF‐γ produced by IL‐12‐stimulated T cells might present BNL tumour antigens and activate DC/BNL‐primed CD4+ cytotoxic T lymphocytes (CTLs) in a MHC class II‐dependent manner, leading to perforin‐mediated bystander killing of neighbouring MHC class II‐negative tumour cells.

Allogeneic MHC Gene Transfer Enhances an Effective Antitumor Immunity in the Early Period of Autologous Hematopoietic Stem Cell Transplantation

“…The flow cytometry detected no MHC class II expression on CT26 cells (data not shown). Several murine bone marrow transplantation models have shown that CD4 + T cells as well as CD8 + T cells are major effectors to induce the graft-versus-host disease and also graft versus tumor effects against MHC II -negative tumor cells, and the inflammatory cytokines such as tumor necrosis factor-a, IFN-g, and interleukin-1 produced by the T cells might contribute to the CD4-mediated killing effect in the MHC class II -independent manner (16,19,20). To further explore the role of immune cells in antitumor immunity in vivo, the mice were administered with anti-CD4, anti-CD8, and anti-asialo GM1 antibodies to deplete these cell populations.…”

Glucocorticoid-Induced TNF Receptor Family Related Gene Activation Overcomes Tolerance/Ignorance to Melanoma Differentiation Antigens and Enhances Antitumor Immunity

“…Studies have shown that CD4 ϩ T cells that infiltrate tumors contain perforin granules and have the potential to kill by Fas/FasL system (36,37). Because class II Ags are expressed in different solid malignancies including melanoma (38,39), CD4…”

The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death

“…This discrepancy can be explained by the fact that anthracycline-mediated anti-cancer therapy relies on two distinct can be efficiently eliminated after co-injection of CRT plus MTX in a setting in which T cells are required for the therapeutic response. This implies that immune effectors can attack other targets in addition to class I (such as class IIrestricted tumor antigen, which is well described for CT26 cells 29,30 ), that low amounts of MHC class I are sufficient to mediate cytotoxic T-cell responses (note that the class I defect is only partial) or that tumors that express low class I levels in vitro acquire MHC class I in vivo as a result of local inflammatory responses. Indeed, animals that had been successfully immunized with MTX-treated CT26 cells and protected against CT26 WT cells also rejected CT26 ERp57 low cells (T Panaretakis, unpublished data).…”