The distinct role of CD4+ and CD8+ T-cells during the anti-tumour effects of targeted superantigens

Abstract

Summary To target T-cells to the tumour area we created a recombinant protein of the bacterial superantigen (SAg) Staphylococcal enterotoxin A (SEA) and the Fab-fragment of a tumour-reactive antibody. This antibody-targeted SAg immunotherapy therapy has been shown to be highly efficient, eliminating > 95% of the pulmonary metastasis in mice carrying established melanoma micrometastases. Earlier studies demonstrated that elimination of the C215-expressing B16-melanoma lung metastasis was dependent on interferon (IFN)-γ release and expression of perforin. In the present study, therapeutic effector functions were analysed both locally at the tumour site and systemically in the spleen. In order to elucidate the role of each T-cell subset during Fab-SEA therapy, CD4 knock-out (KO) and CD8 KO mice were used. Tumour size reduction was statistically significant in Fab-SEA-based tumour therapy in both types of T-cell-deficient mice compared to wildtype mice. CD4 KO mice displayed a drastic reduction in the number of tumour-infiltrating macrophages and CD8 + T-cells. Therapy-induced accumulation of perforin-containing cells at the tumour site was significantly impaired in CD8 KO mice, and marginally in CD4 KO mice. Moreover, CD4 KO mice failed to produce substantial amounts of the tumour suppressive cytokine IFN-γ. This is in sharp contrast to normal mice where a massive local release was recorded. CD8 KO mice displayed a spontaneous production of interleukin (IL)-4 and IL-10 locally in the tumour. Neither normal nor CD4 KO mice produced detectable levels of these Th-2-associated cytokines. The high level of IL-10 was demonstrated to inhibit Fab-SEA tumour therapy, since the therapeutic efficacy was significantly higher in IL-10 KO mice. These results illustrate the importance of a finely tuned cellular collaboration to regulate the various phases of an efficient anti-tumour immune response.

The Apoptotic Ligands TRAIL, TWEAK, and Fas Ligand Mediate Monocyte Death Induced by Autologous Lupus T Cells

“…Because our previously published studies show that anti-class II Abs can completely abrogate T cell-mediated autologous monocyte cytotoxicity and anti-class I was less effective (9), we propose that CD4 ϩ T cells are required for the killing, although CD8 ϩ T cells may play an additional role, since CD4 ϩ T cells alone kill less efficiently than unfractionated T cells. The importance of a finely tuned cellular collaboration between CD4 ϩ and CD8 ϩ T cells for cytotoxicity has been described by other groups (32)(33)(34). We had previously shown that this phenomenon is specific for autologous monocytes, since SLE T cells do not kill allogeneic monocytes from normal or other lupus patients, and the killing was inhibited with mAbs to class II MHC determinants (9).…”

Intratumoral IL-18 gene transfer improves therapeutic efficacy of antibody-targeted superantigen in established murine melanoma

“…44 In addition, it was recently demonstrated that T cell receptor triggering in the presence of IL-10 inhibited IFN-␥ production in freshly isolated CD4 + T cells 45 and downregulated the expression of granzyme B. 40,46 The production of IL-4 in the tumor-bearing C57BL/6 mice treated with C215Fab-SEA alone increased as compared with that of mice in control groups, while the level of IL-4 in mice treated with AdIL-18 alone was lower that in mice of control groups. After the combined treatment with C215Fab-SEA/Ad IL-18, the IL-4 level of tumorbearing C57BL/6 mice decreased as compared with that in mice treated with C215Fab-SEA alone.…”

“…It was shown to suppress both IFN-␥ production and the antitumor effector phase of IFN-␥. [39][40][41] It may inhibit and down-regulate MHC-II molecule expression of monocytes as well as interfere with antigen presentation, 42 inhibit the up-regulation of co-stimulatory molecules 43 and suppress the cytotoxicity of macrophages. 44 In addition, it was recently demonstrated that T cell receptor triggering in the presence of IL-10 inhibited IFN-␥ production in freshly isolated CD4 + T cells 45 and downregulated the expression of granzyme B.…”

A phase II study of a 5T4 oncofoetal antigen tumour-targeted superantigen (ABR-214936) therapy in patients with advanced renal cell carcinoma

“…Activation leads to the expression of perforin and the production of cytotoxic and proinflammatory cytokines and thus death of the APC (Fischer et al, 1990;Dohlsten et al, 1991b). Targeting of superantigens towards tumours induces a strong, local cytotoxic T-cell attack, which directly kills tumour cells and leads to inflammation and the local accumulation of tumouricidal cytokines (Dohlsten et al, 1991a(Dohlsten et al, , 1994(Dohlsten et al, , 1995Litton et al, 1997Litton et al, ,1999.…”