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Institute for Cellular Therapeutics and Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202
Tumors use a complex set of direct and indirect mechanisms to evade the immune system. Naturally arising CD4+CD25+FoxP3+ T regulatory (Treg) cells have been implicated recently in tumor immune escape mechanism, but the relative contribution of these cells to overall tumor progression compared with other immune evasion mechanisms remains to be elucidated. Using the A20 B cell lymphoma as a transplantable tumor model, we demonstrate that this tumor employs multiple direct (expression of immunoinhibitory molecule PD-L1, IDO, and IL-10, and lack of expression of CD80 costimulatory molecule) and indirect (down-regulation of APC function and induction of Treg cells) immune evasion mechanisms. Importantly, Treg cells served as the dominant immune escape mechanism early in tumor progression because the physical elimination of these cells before tumor challenge resulted in tumor-free survival in 70% of mice, whereas their depletion in animals with established tumors had no therapeutic effect. Therefore, our data suggest that Treg cells may serve as an important therapeutic target for patients with early stages of cancer and that more vigorous combinatorial approaches simultaneously targeting multiple immune evasion as well as immunosurveillance mechanisms for the generation of a productive immune response against tumor may be required for effective immunotherapy in patients with advanced disease.
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 funded in parts by grants from Kentucky Lung Cancer Research Program, National Institutes of Health/National Cancer Institute Grant R43 CA109866, and the Commonwealth of Kentucky Research Challenge Trust Fund.
2 Address correspondence and reprint requests to Dr. Haval Shirwan, Institute for Cellular Therapeutics, 570 South Preston Street, Donald Baxter Biomedical Building, Suite 404E, University of Louisville, Louisville, KY 40202. E-mail address: haval.shirwan{at}louisville.edu
3 Abbreviations used in this paper: Treg, T regulatory; 1-MT, 1-methyl-D-tryptophan; DC, dendritic cell; DP, double positive; HPRT, hypoxanthine phosphoribosyltransferase; SP, single positive; Teff, T effector.
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