The Journal of Experimental Medicine
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Published 20 September 2004. doi:10.1084/jem.20041130
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 6, 771-782
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Concomitant Tumor Immunity to a Poorly Immunogenic Melanoma Is Prevented by Regulatory T Cells

Mary Jo Turk, José A. Guevara-Patiño, Gabrielle A. Rizzuto, Manuel E. Engelhorn, and Alan N. Houghton

The Swim Across America Laboratory of Tumor Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Address correspondence to Alan N. Houghton, The Swim Across America Laboratory of Tumor Immunology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Phone: (212) 639-7595; Fax: (212) 794-4352; email: a-houghton{at}ski.mskcc.org

Concomitant tumor immunity describes immune responses in a host with a progressive tumor that rejects the same tumor at a remote site. In this work, concomitant tumor immunity was investigated in mice bearing poorly immunogenic B16 melanoma. Progression of B16 tumors did not spontaneously elicit concomitant immunity. However, depletion of CD4+ T cells in tumor-bearing mice resulted in CD8+ T cell–mediated rejection of challenge tumors given on day 6. Concomitant immunity was also elicited by treatment with cyclophosphamide or DTA-1 monoclonal antibody against the glucocorticoid-induced tumor necrosis factor receptor. Immunity elicited by B16 melanoma cross-reacted with a distinct syngeneic melanoma, but not with nonmelanoma tumors. Furthermore, CD8+ T cells from mice with concomitant immunity specifically responded to major histocompatibility complex class I–restricted epitopes of two melanocyte differentiation antigens. RAG1–/– mice adoptively transferred with CD8+ and CD4+ T cells lacking the CD4+CD25+ compartment mounted robust concomitant immunity, which was suppressed by readdition of CD4+CD25+ cells. Naturally occurring CD4+CD25+ T cells efficiently suppressed concomitant immunity mediated by previously activated CD8+ T cells, demonstrating that precursor regulatory T cells in naive hosts give rise to effective suppressors. These results show that regulatory T cells are the major regulators of concomitant tumor immunity against this weakly immunogenic tumor.

Key Words: melanocyte differentiation antigen • cancer immunity • immune suppression • GITR • cyclophosphamide

Abbreviations used in this paper: GITR, glucocorticoid-induced TNF receptor; mAb, monoclonal antibody.


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