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Chronic Immune Therapy Induces a Progressive Increase in Intratumoral T Suppressor Activity and a Concurrent Loss of Tumor-Specific CD8⁺ T Effectors in her-2/neu Transgenic Mice Bearing Advanced Spontaneous Tumors¹

James Graham Brown Cancer Center and Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202

A single intratumoral injection of IL-12 and GM-CSF-encapsulated microspheres induces the complete regression of advanced spontaneous tumors in her-2/neu transgenic mice. However, tumor regression in this model is transient and long-term cure is not achieved due to recurrence. Posttherapy molecular analysis of immune activation/suppression markers within the tumor microenvironment demonstrated a dramatic up-regulation of IFN- and a concomitant down-regulation of Forkhead/winged-helix protein 3 (Foxp3), TGF, and IL-10 expression. Therapy-induced reversion of immune suppression was transient since all three markers of suppression recovered rapidly and surpassed pretherapy levels by day 7 after treatment, resulting in tumor resurgence. Repeated treatment enhanced short-term tumor regression, but did not augment long-term survival. Serial long-term analysis demonstrated that although chronic stimulation enhanced the IFN- response, this was countered by a parallel increase in Foxp3, TGF, and IL-10 expression. Analysis of tumor-infiltrating T lymphocyte populations showed that the expression of Foxp3 and IL-10 was associated with CD4⁺CD25⁺ T cells. Repeated treatment resulted in a progressive increase in tumor-infiltrating CD4⁺CD25⁺Foxp3⁺ T suppressor cells establishing their role in long-term neutralization of antitumor activity. Analysis of tumor-infiltrating CD8⁺ T cells demonstrated that although treatment enhanced IFN- production, antitumor cytotoxicity was diminished. Monitoring of CD8⁺ T cells that specifically recognized a dominant MHC class I her-2/neu peptide showed a dramatic increase in tetramer-specific CD8⁺ T cells after the first treatment; however, continuous therapy resulted in the loss of this population. These results demonstrate that both enhanced suppressor activity and deletion of tumor-specific T cells are responsible for the progressive loss of efficacy that is associated with chronic immune therapy.

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				K. Leon, K. Garcia, J. Carneiro, and A. Lage How Regulatory CD25+CD4+ T Cells Impinge on Tumor Immunobiology: The Differential Response of Tumors to Therapies J. Immunol., November 1, 2007; 179(9): 5659 - 5668. [Abstract] [Full Text] [PDF]