The distinct role of CD4+ and CD8+ T-cells during the anti-tumour effects of targeted superantigens.
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)-gamma 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 wild-type 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-gamma. 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.
Litton
M J
MJ
Department of Immunology, Wenner-Gren's Institute, Stockholm University, Sweden.
Dohlsten
M
M
Rosendahl
A
A
Ohlsson
L
L
Søgaard
M
M
Andersson
J
J
Andersson
U
U
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004768:Enterotoxins; D007091:Image Processing, Computer-Assisted; D007140:Immunoglobulin Fab Fragments; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013154:Spleen / Q000276:immunology; D018089:Superantigens / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D004768:Enterotoxins; D007140:Immunoglobulin Fab Fragments; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D018089:Superantigens; D054353:Perforin; D016753:Interleukin-10; C026066:enterotoxin A, Staphylococcal; D007371:Interferon-gamma