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CD8⁺ T Cells Induce Complete Regression of Advanced Ovarian Cancers by an Interleukin (IL)-2/IL-15–Dependent Mechanism

Authors' Affiliations: ¹ Deeley Research Centre, British Columbia Cancer Agency, and University of Victoria, Victoria, British Columbia, Canada and ² Seattle Biomedical Research Institute, Seattle, Washington

Requests for reprints: Brad H. Nelson, British Columbia Cancer Agency, 2410 Lee Avenue, Victoria, British Columbia, Canada V8R 6V5. Phone: 250-519-5705; Fax: 250-519-2004; E-mail: bnelson{at}bccancer.bc.ca.

Purpose: In vitro studies suggest that ovarian cancer evades immune rejection by fostering an immunosuppressive environment within the peritoneum; however, the functional responses of ovarian cancer–specific T cells have not been directly investigated in vivo. Therefore, we developed a new murine model to enable tracking of tumor-specific CD8⁺ T-cell responses to advanced ovarian tumors.

Experimental Design: The ovarian tumor cell line ID8 was transfected to stably express an epitope-tagged version of HER-2/neu (designated Neu^OT-I/OT-II). After i.p. injection into C57BL/6 mice, ID8 cells expressing Neu^OT-I/OT-II gave rise to disseminated serous adenocarcinomas with extensive ascites. CD8⁺ T cells expressing a transgenic T-cell receptor specific for the OT-I epitope of Neu^OT-I/OT-II were adoptively transferred into tumor-bearing mice, and functional responses were monitored. Cytokine signaling requirements were evaluated by comparing the responses of wild-type donor T cells with those with genetic deletion of the interleukin (IL)-2/IL-15 receptor β subunit (CD122) or the IL-2 receptor subunit (CD25).

Results: On adoptive transfer into tumor-bearing hosts, wild-type OT-I T cells underwent a striking proliferative response, reaching peak densities of 40% and 90% of CD8⁺ T cells in peripheral blood and ascites, respectively. OT-I cells infiltrated and destroyed tumor tissue, and ascites completely resolved within 10 days. By contrast, CD122^–/– OT-I cells and CD25^–/– OT-I cells proliferated in blood but failed to accumulate in ascites or tumor tissue or induce tumor regression.

Conclusions: Contrary to expectation, advanced ovarian cancers can support extraordinary CD8⁺ T-cell proliferation and antitumor activity through an IL-2/IL-15–dependent mechanism.