Antibody‐targeted superantigen therapy induces tumor‐infiltrating lymphocytes, excessive cytokine production, and apoptosis in human colon carcinoma

Litton, Mark J.; Dohlsten, Mikael; Lando, Peter A.; Kalland, Terje; Ohlsson, Lennart; Andersson, Jan; Andersson, Ulf

doi:10.1002/eji.1830260102

Cited by 57 publications

(33 citation statements)

References 46 publications

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“…The results showed that CD8 KO mice mounted a stronger anti-tumour response after Fab-SEA therapy than CD4 KO mice. These results are in line with the previous findings that Fab-SEA therapy was unsuccessful in severe combined immune deficient (SCID) mice and nude mice, deficient of T-cells (Litton et al, 1996). Thus, T-cells are important mediators in SAg-targeted therapy.…”

Section: Discussionsupporting

confidence: 91%

“…SAg have, in contrast to conventional peptide antigens, a unique capacity of activating both subsets of Tcells (Herrmann et al, 1990;Dohlsten et al, 1990). In fact, it has been demonstrated previously that both CD4 + and CD8 + T-cells are recruited to the tumour area in response to antibody-targeted SAg tumour therapy (Dohlsten et al, 1995a;Litton et al, 1996Litton et al, , 1997Rosendahl et al, 1998a). However, both subsets have the potential to regulate helper activity as well as cytotoxic functions.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1999

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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

et al. 1999

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“…Our present study confirmed that Kupffer cells isolated from cirrhotic rat livers expressed elevated levels of TNFα and IL-1α mRNA. As tumour necrosis factor and interleukin-1 have been shown to enhance the level of FasR expression on cell surfaces (Litton et al, 1996;Moulian et al, 1999), we suggest that over-production of these cytokines by Kupffer cells in cirrhotic livers probably accounts for their modulating effects on colon cancer cells. However, further studies are needed to assess the regulating effects of cytokines and growth factors produced by Kupffer cells in cirrhotic liver on FasR-sensitivity of colon cancer cells.…”

Section: Discussionmentioning

confidence: 57%

Kupffer cells of cirrhotic rat livers sensitize colon cancer cells to Fas-mediated apoptosis

et al. 2001

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Summary Metastasis of colorectal carcinomas rarely occurs in cirrhotic livers. Our study investigated the influence of activated Kupffer cells from cirrhotic rat livers on hepatic colonization and FasR-mediated apoptosis of colon cancer cells. A rat colon cancer cell line, RCN-9, was used to inoculate rat livers. Treatment with conditioned media of Kupffer cells isolated from CCl 4 -induced cirrhotic rat livers (cirrhotic KCM) significantly reduced the incidence of hepatic colonization of RCN-9 cells. In vitro cytotoxicity of Kupffer cells and tumour infiltrating lymphocytes (TILs) on RCN-9 cells was evaluated using [ 3 H]-release assay. RCN-9 cells were resistant to cytotoxicity mediated by cirrhotic Kupffer cells, but were sensitized to TIL-mediated killing after treatment with cirrhotic KCM. The specific killing induced by TILs was FasR-mediated, as it was inhibited by ZB4, an antagonistic anti-FasR antibody. In agreement, cirrhotic KCM increased recombinant Fas ligand-induced apoptosis of RCN-9 cells, and up-regulated FasR expression on RCN-9 cells as evaluated by RT-PCR and flow cytometry. These findings suggest that Kupffer cells in cirrhotic livers sensitize metastatic colon cancer cells to FasR-mediated apoptosis by up-regulating the receptors, which thus prepare them to be eliminated by infiltrating lymphocytes.

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“…Targeting of superantigens has previously been described for colon cancer therapy (Dohlsten et al, 1994(Dohlsten et al, , 1995b. This therapy leads to infiltration of T-cells in the tumour tissue (Dohlsten et al, 1995a, Litton et al, 1996. Superantigen therapy stimulates both CD4+ and CD8+ T-cells (Dohlsten et al, 1995a) that have potent cytotoxic properties to directly kill target cells, but secondary effects such as cytokine secretion and recruitment of other effector cells may be of even higher importance for successful therapy.…”

Section: Discussionmentioning

confidence: 99%

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

et al. 2001

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Summary Superantigens activate T-cells by linking the T-cell receptor to MHC class II on antigen-presenting cells, and novel reactivity can be introduced by fusing the superantigen to a targeting molecule. Thus, an antibody-targeted superantigen, which activates T cells to destroy tumour cells, might be used as cancer therapy. A suitable target is the 5T4 oncofetal antigen, which is expressed on many carcinomas. We constructed a fusion protein from a Fab of a monoclonal antibody recognizing the 5T4 antigen, and an engineered superantigen. The recombinant product 5T4FabV13-SEA D227A bound the 5T4 antigen expressed on the human non-small-cell lung cancer cell line Calu-1 with a K d of 1.2 nM while the substitution of Asp227 to Ala in the superantigen moiety reduced binding activity to MHC class II. 5T4FabV13-SEA D227A tumour reactivity was demonstrated in 7/7 NSCLC samples by immunohistochemistry, while normal tissue reactivity was low to moderate. 5T4FabV13-SEA D227A induced significant T-cell-dependent in vitro killing of sensitive 5T4 bearing Calu-1 cells, with maximum lysis at 10 -10 M, while the capacity to lyse MHC class II expressing cells was approximately 1000 times less effective. Immunotherapy of 5T4FabV13-SEA D227A against human NSCLC was investigated in SCID mice reconstituted with human peripheral blood mononuclear cells. Mice carrying intreperitoneally growing Calu-1 cells showed significant reduction in tumour mass and number after intravenous therapy with 5T4FabV13-SEA D227A . Thus, 5T4FabV13-SEA D227A has highly attractive properties for therapy of human NSCLC.

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Antibody‐targeted superantigen therapy induces tumor‐infiltrating lymphocytes, excessive cytokine production, and apoptosis in human colon carcinoma

Cited by 57 publications

References 46 publications

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

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

Kupffer cells of cirrhotic rat livers sensitize colon cancer cells to Fas-mediated apoptosis

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

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