CD8+ T cells induce complete regression of advanced ovarian cancers by an Interleukin (IL)-2/IL-15-dependent mechanism

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 beta subunit (CD122) or the IL-2 receptor alpha subunit (CD25). Results: On adoptive transfer into tumor-bearing hosts, wild-type OT-I Tcells underwent a striking proliferative response, reaching peak densities of similar to 40% and similar to 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.