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Functional T Cell Responses to Tumor Antigens in Breast Cancer Patients Have a Distinct Phenotype and Cytokine Signature¹

Margaret Inokuma^*, Corazon dela Rosa, Charles Schmitt, Perry Haaland, Janet Siebert, Douglas Petry^*, MengXiang Tang^*, Maria A. Suni^*, Smita A. Ghanekar^*, Daiva Gladding^*, John F. Dunne^*, Vernon C. Maino^*, Mary L. Disis and Holden T. Maecker^2,*

^* BD Biosciences, San Jose, CA 95131; University of Washington, Seattle, WA 98109; BD Technologies, Research Triangle Park, NC 27709; and CytoAnalytics, Denver, CO 80209

The overall prevalence with which endogenous tumor Ags induce host T cell responses is unclear. Even when such responses are detected, they do not usually result in spontaneous remission of the cancer. We hypothesized that this might be associated with a predominant phenotype and/or cytokine profile of tumor-specific responses that is different from protective T cell responses to other chronic Ags, such as CMV. We detected significant T cell responses to CEA, HER-2/neu, and/or MAGE-A3 in 17 of 21 breast cancer patients naive to immunotherapy. The pattern of T cell cytokines produced in response to tumor-associated Ags (TAAs) in breast cancer patients was significantly different from that produced in response to CMV or influenza in the same patients. Specifically, there was a higher proportion of IL-2-producing CD8⁺ T cells, and a lower proportion of IFN--producing CD4⁺ and/or CD8⁺ T cells responding to TAAs compared with CMV or influenza Ags. Finally, the phenotype of TAA-responsive CD8⁺ T cells in breast cancer patients was almost completely CD28⁺CD45RA^– (memory phenotype). CMV-responsive CD8⁺ T cells in the same patients were broadly distributed among phenotypes, and contained a high proportion of terminal effector cells (CD27^–CD28^–CD45RA⁺) that were absent in the TAA responses. Taken together, these results suggest that TAA-responsive T cells are induced in breast cancer patients, but those T cells are phenotypically and functionally different from CMV- or influenza-responsive T cells. Immunotherapies directed against TAAs may need to alter these T cell signatures to be effective.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant U54 CA090818, and M.I. is supported in part by Grant RO.

² Address correspondence and reprint requests to Dr. Holden Maecker, BD Biosciences, 2350 Qume Drive, San Jose, CA 95131. E-mail address: holden_maecker{at}bd.com

³ Abbreviations used in this paper: TAA, tumor-associated Ag; BFA, brefeldin A; ICS, intracellular staining.

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