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 tumors.
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-gamma and a concomitant down-regulation of Forkhead/winged-helix protein 3 (Foxp3), TGFbeta, 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-gamma response, this was countered by a parallel increase in Foxp3, TGFbeta, 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-gamma 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.
Nair
Raji E
RE
James Graham Brown Cancer Center and Department of Microbiology and Immunology, School of Medicine, University of Louisville, KY 40202, USA.
Kilinc
Mehmet O
MO
Jones
Stacy A
SA
Egilmez
Nejat K
NK
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D018734:Genes, erbB-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000627:therapeutic use; D016233:Immunotherapy, Active / Q000379:methods; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000008:administration & dosage / Q000627:therapeutic use; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D018984:Epitopes, T-Lymphocyte; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor