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Regulates Donor CD8 T Cell Expansion, Migration, and Leads to Apoptosis of Cells of a Solid Tumor1
* Trudeau Institute, Saranac Lake, NY 12983; and
Cell and Molecular Biology Program, University of Vermont, Burlington, VT 05405
We previously reported that IFN-
secreted by donor cytotoxic T cell 1 (Tc1) cells was the most important factor in promoting EG7 (an OVA transfection the EL4 thymoma) rejection in mice. In this study, we show that the ability of the host to respond to Tc1-secreted IFN- is critical for promoting acute tumor rejection, while host production of IFN- is not important. CFSE-labeled wild-type and IFN--deficient Tc1 cells divide rapidly in secondary lymphoid organs, indicating no defect in rate of cell division. However, wild-type Tc1 cells accumulate to significantly greater numbers in the tumor than deficient Tc1 cells. Hosts injected with wild-type Tc1 effectors had more T cells within the tumor at day 4, had higher levels of MCP-1, IFN--inducible protein-10, MIP-1
, and MIP-1
mRNA transcripts, had greater numbers of CD11b+ and Gr-1+ cells within the tumor, and had massive regions of tumor cell apoptosis as compared with IFN- knockout Tc1 cell-treated hosts. NO has a cytostatic effect on EG7 growth in vitro, and NO is important for tumor eradication by day 22. These observations are compatible with a model in which the donor CD8 Tc1 effectors expand rapidly in the host, migrate to the tumor site, and induce the secretion of a number of chemokines that in turn recruit host cells that then attack the tumor.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant CA71833 and the Trudeau Institute.
2 Current address: Department of Immunology, Sidney Kimmel Cancer Center, San Diego, CA 92131.
3 Address correspondence and reprint requests to Dr. Richard W. Dutton, Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983. E-mail address: dutton{at}northnet.org
4 Abbreviations used in this paper: Tc, cytotoxic T cell; iNOS, IFN--inducible NO synthase; IP-10, IFN--inducible protein-10; FasL, Fas ligand; LT-, lymphotoxin-; KO, knockout; DLN, draining lymph node; PAC, peritoneal adherent cell.
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