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

Abstract

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 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.

• Authors: Taimei Yang, Erika M Wall, Katy Milne, Patty Theiss, Peter Watson, Brad H Nelson
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 23 Pg. 7172-80 (Dec 01 2007) ISSN: 1078-0432 [Print] United States
• PMID: 18056198 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Interleukin-15
• Interleukin-2

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Female
• Immunotherapy, Adoptive (methods)
• Interleukin-15 (immunology, metabolism)
• Interleukin-2 (immunology, metabolism)
• Lymphocyte Activation (immunology)
• Mice
• Mice, Inbred C57BL
• Neoplasm Staging
• Ovarian Neoplasms (immunology, therapy)
• Rats