Central Role of IFNγ–Indoleamine 2,3-Dioxygenase Axis in Regulation of Interleukin-12–Mediated Antitumor Immunity
| Autor: | Rachael B. Rowswell-Turner, Nejat K. Egilmez, Tao Gu, Mehmet O. Kilinc |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
T-Lymphocytes medicine.medical_treatment Biology Article Immune tolerance Interferon-gamma Mice Lymphocytes Tumor-Infiltrating T-Lymphocyte Subsets Immune Tolerance medicine Animals Indoleamine-Pyrrole 2 3 -Dioxygenase Interferon gamma IL-2 receptor Indoleamine 2 3-dioxygenase Mice Knockout Mice Inbred BALB C Tumor microenvironment Reverse Transcriptase Polymerase Chain Reaction FOXP3 Neoplasms Experimental Flow Cytometry Interleukin-12 Cytokine Oncology Immunology Cancer research Interleukin 12 medicine.drug |
| Zdroj: | Cancer Research. 70:129-138 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Sustained intratumoral delivery of interleukin-12 (IL-12) and granulocyte macrophage colony-stimulating factor induces tumor regression via restoration of tumor-resident CD8+ T-effector/memory cell cytotoxicity and subsequent repriming of a secondary CD8+ T-effector cell response in tumor-draining lymph nodes (TDLN). However, treatment-induced T-effector activity is transient and is accompanied with a CD4+ CD25+ Foxp3+ T-suppressor cell rebound. Molecular and cellular changes in posttherapy tumor microenvironment and TDLN were monitored to elucidate the mechanism of counterregulation. Real-time PCR analysis revealed a 5-fold enhancement of indoleamine 2,3-dioxygenase (IDO) expression in the tumor and the TDLN after treatment. IDO induction required IFNγ and persisted for up to 7 days. Administration of the IDO inhibitor d-1-methyl tryptophan concurrent with treatment resulted in a dramatic enhancement of tumor regression. Enhanced efficacy was associated with a diminished T-suppressor cell rebound, revealing a link between IDO activity and posttherapy regulation. Further analysis established that abrogation of the regulatory counterresponse resulted in a 10-fold increase in the intratumoral CD8+ T-cell to CD4+ Foxp3+ T-cell ratio. The ratio of proliferating CD8+ T-effector to CD4+ Foxp3+ T-suppressor cells was prognostic for efficacy of tumor suppression in individual mice. IFNγ-dependent IDO induction and T-suppressor cell expansion were primarily driven by IL-12. These findings show a critical role for IDO in the regulation of IL-12–mediated antitumor immune responses. Cancer Res; 70(1); 129–38. |
| Databáze: | OpenAIRE |
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