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Tumor Recognition and Self-Recognition Induce Distinct Transcriptional Profiles in Antigen-Specific CD4 T Cells ¹

Derese Getnet^*, Charles H. Maris^2,*, Edward L. Hipkiss^*, Joseph F. Grosso^*, Timothy J. Harris^*, Hung-Rong Yen^*,, Tullia C. Bruno^*, Satoshi Wada^*, Adam Adler, Robert W. Georgantas^*, Chunfa Jie, Monica V. Goldberg^*, Drew M. Pardoll^* and Charles G. Drake^3,*,¶

^* Department of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231; Graduate Institute of Clinical Medical Sciences, College of Medicine Chang Gung University, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Center for Immunotherapy of Cancer and Infectious Diseases and Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030; Analysis Unit, Johns Hopkins Medical Institute Microarray Core Facility, Baltimore, MD 21205; and ^¶ Brady Urological Institute, Johns Hopkins University, Baltimore, MD 21218

Tumors express a wide variety of both mutated and nonmutated Ags. Whether these tumor Ags are broadly recognized as self or foreign by the immune system is currently unclear. Using an autochthonous prostate cancer model in which hemagglutinin (HA) is specifically expressed in the tumor (ProHA x TRAMP mice), as well as an analogous model wherein HA is expressed in normal tissues as a model self-Ag (C3HA^high), we examined the transcriptional profile of CD4 T cells undergoing Ag-specific division. Consistent with our previous data, transfer of Ag-specific CD4 T cells into C3HA^high resulted in a functionally inactivated CD4 T cell profile. Conversely, adoptive transfer of an identical CD4 T cell population into ProHA x TRAMP mice resulted in the induction of a regulatory phenotype of the T cell (Treg) both at the transcriptional and functional level. Interestingly, this Treg skewing was a property of even early-stage tumors, suggesting Treg induction as an important tolerance mechanism during tumor development.

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¹ This work was supported by National Institutes of Health Grants R01 CA127153 (to C.G.D.) and K08 CA096948 (to C.G.D.) and by the Patrick C. Walsh Fund. C.G.D. is a Damon Runyon-Lilly Clinical Investigator. D.M.P. is a Januey Scholar, holds the Seraph Chair for Cancer Research, and is supported in part by gifts from William and Betty Toperer, Dorothy Needle, and the Commonwealth Foundation.

² Current address: Midwest Research Institute, Rockville, MD 20850.

³ Address correspondence and reprint requests to Dr. Charles G. Drake, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, 1650 Orleans Street, CRB I No. 410, Baltimore, MD 21231. E-mail address: drakech{at}jhmi.edu

⁴ Abbreviations used in this paper: HA, hemagglutinin; TRAMP, transgenic adenocarcinoma of the mouse prostate; PIN, prostatic intraepithelial neoplasia; Treg, regulatory T cell; VaccHA, Vaccinia-hemagglutinin; LMHA, Listeria monocytogenes-HA; DC, dendritic cell.

⁵ The online version of this article contains supplemental material.