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Tumor-Induced Immune Suppression of In vivo Effector T-Cell Priming Is Mediated by the B7-H1/PD-1 Axis and Transforming Growth Factor β

¹ University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan; ² Institute of Gastroenterology of Hofu, Yamaguchi, Japan; and ³ Department of Dermatology and Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland

Requests for reprints: Alfred Chang, 3302 Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI, 48109-0932. Phone: 734-936-4392; Fax: 734-647-9647; E-mail: aechang{at}umich.edu.

Key Words: adoptive immunotherapy • B7-H1 • TGF-β • PD-1 • Tregs

We have generated effector T cells from tumor-draining lymph nodes (TDLN) that are efficacious in adoptive immunotherapy. We now examine the effect of concomitant tumors on the generation of effector T cells. We inoculated methylcholanthrene (MCA) 205 in the flanks of normal mice and mice bearing MCA 205 lung metastases. TDLN cells from these mice were activated and expanded in vitro, and adoptively transferred to mice bearing lung metastases. Effector T cells generated from TDLN in mice with only flank tumor mediated potent antitumor activity. However, antitumor efficacy of the effector T cells generated from TDLN in mice with pre-existent lung tumor (cTDLN) was reduced. Phenotyping studies showed that dendritic cells in cTDLN expressed higher levels of B7-H1, whereas cTDLN T cells expressed higher levels of PD-1. The levels of IFN were reduced, and the levels of CD4⁺Foxp3⁺ regulatory T cells were increased in cTDLN versus TDLN. The in vitro activation of cTDLN was increased by blocking B7-H1 or transforming growth factor (TGF)-β. Importantly, we found a synergistic up-regulation of IFN with simultaneous blockade of B7-H1 and TGF-β that was much greater than observed with TDLN. In vitro activation of cTDLN with anti–B7-H1 and anti–TGF-β and in vivo administration of these antibodies after adoptive transfer resulted in the abrogation of the suppression associated with cTDLN. These results show a major role for the B7-H1/PD-1 axis and TGF-β as synergistic suppressive mechanisms in cTDLN. Our data have clinical relevance in the generation of effector T cells in the tumor-bearing host. [Cancer Res 2008;68(13):5432–7]

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