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Enhanced Induction of Antitumor T-Cell Responses by Cytotoxic T Lymphocyte-associated Molecule-4 Blockade: The Effect Is Manifested Only at the Restricted Tumor-bearing Stages¹

Biomedical Research Center, Osaka University Medical School, 2-2, Yamada-oka, Suita, Osaka 565, Japan [Y-F. Y., J-P. Z., J. M., R. W., S. O., H. F., T. H.]; and The University of Chicago, Chicago, Illinois 60637 [T. W., J. B.]

Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), a second counterreceptor for the B7 family of costimulatory molecules, functions as a negative regulator of T-cell activation. Here, we investigated whether the blockade of the CTLA-4 function leads to enhancement of antitumor T-cell responses at various stages of tumor growth. Unfractionated spleen cells taken from CSA1M fibrosarcoma-bearing mice 1–2 weeks after CSA1M cell implantation (early tumor-bearing mice) contained tumor-primed T cells that produced interleukin 2 and IFN- through collaboration with antigen-presenting cell-binding tumor antigens when cultured in vitro. However, this initial lymphokine-producing capacity decreased at later stages of tumor growth (7–10 weeks after tumor cell implantation). Anti-CTLA-4 monoclonal antibody (mAb) was added to whole-spleen cell cultures from early or late tumor-bearing mice. Spleen cells from early tumor-bearing mice exhibited enhanced production of interleukin 2 and IFN- upon in vitro culture in the presence of anti-CTLA-4 mAb. However, addition of anti-CTLA-4 mAb to whole-spleen cell cultures from late tumor-bearing mice failed to display such an enhancement. Consistent with these in vitro results, the in vivo antitumor effect of anti-CTLA-4 administration was observed in a tumor-bearing stage-restricted manner; in vivo administration of anti-CTLA-4 (1 mg/mouse, three times at 1-week intervals) into early tumor-bearing mice resulted in regression of growing tumors, whereas the same treatment did not affect tumor growth when performed for late tumor-bearing mice. Similar anti-CTLA-4 effect was observed in another tumor (OV-HM ovarian carcinoma) model. These in vitro and in vivo results indicate that CTLA-4 blockade in tumor-bearing individuals enhances the capacity to generate antitumor T-cell responses, but the expression of such an enhancing effect is restricted to early stages of tumor growth.

¹ This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan, and, in part, by Bluestone Grant (United States Public Health Service) P01 A135294.

² To whom requests for reprints should be addressed. Phone: 81-06-879-3982; Fax: 81-06-879-3989.

Received 3/28/97. Accepted 7/16/97.

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