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


METHODS
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 T cells underwent a striking proliferative response, reaching peak densities of approximately 40% and approximately 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.
Deeley Research Centre, British Columbia Cancer Agency, University of Victoria, Victoria, British Columbia, Canada.
Taimei
T
Yang
Erika M
EM
Wall
Katy
K
Milne
Patty
P
Theiss
Peter
P
Watson
Brad H
BH
Nelson
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods*; D019409:Interleukin-15 / Q000276:immunology* / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000628:therapy*; D051381:Rats
D019409:Interleukin-15; D007376:Interleukin-2