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IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma
Zhi-Zhang Yang, … , Thomas E. Witzig, Stephen M. Ansell
Zhi-Zhang Yang, … , Thomas E. Witzig, Stephen M. Ansell
Published March 19, 2012
Citation Information: J Clin Invest. 2012;122(4):1271-1282. https://doi.org/10.1172/JCI59806.
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Research Article Oncology Article has an altmetric score of 20

IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma

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Abstract

The cytokine IL-12 induces IFN-γ production by T and NK cells. In preclinical models, it contributes to antitumor immunity. However, in clinical testing, it has shown limited benefit in patients with any one of a variety of malignancies. Moreover, in a clinical trial testing a combination of IL-12 and rituximab in patients with follicular B cell non-Hodgkin lymphoma (FL), those treated with IL-12 showed a lower response rate, suggesting that IL-12 actually plays a detrimental role. Here, we investigated whether the failure of IL-12 treatment for FL was due to T cell exhaustion, a condition characterized by reduced T cell differentiation, proliferation, and function, which has been observed in chronic viral infection. We found that extended exposure to IL-12 induced T cell exhaustion and contributed to the poor prognosis in FL patients. Long-term exposure of freshly isolated human CD4+ T cells to IL-12 in vitro caused T cell dysfunction and induced expression of TIM-3, a T cell immunoglobulin and mucin domain protein with a known role in T cell exhaustion, via an IFN-γ–independent mechanism. TIM-3 was required for the negative effect of IL-12 on T cell function. Importantly, TIM-3 also was highly expressed on intratumoral T cells that displayed marked functional impairment. Our findings identify IL-12– and TIM-3–mediated exhaustion of T cells as a mechanism for poor clinical outcome when IL-12 is administered to FL patients.

Authors

Zhi-Zhang Yang, Deanna M. Grote, Steven C. Ziesmer, Toshiro Niki, Mitsuomi Hirashima, Anne J. Novak, Thomas E. Witzig, Stephen M. Ansell

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Figure 1

IL-12 serum levels and their correlation with survival in FL.

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IL-12 serum levels and their correlation with survival in FL.
(A) IL-12 ...
(A) IL-12 serum levels in untreated FL patients (FL, average: 0.56 ± 0.05 ng/ml, n = 30) and healthy donors (HD, average: 0.39 ± 0.049 ng/ml, n = 22, P = 0.017). IL-12 serum levels were measured by multiplex ELISA (Luminex). (B) A Kaplan-Meier curve for progression-free survival by serum levels of IL-12 in FL patients with a cutoff of 0.56 ng/ml (n = 30). (C) Detection of the source of IL-12 levels measured by ELISA in culture supernatants of CD3+ T cells (white), CD19+ B cells (dark gray), or monocytes (black) treated with IFN-γ plus LPS from healthy donors and FL patients. The figure shown is representative of 3 samples. (D) IL-12 production in subsets of T cells, B cells, and monocytes. Freshly isolated MCs from healthy individuals (upper panel) or FL patients (lower panel) were stimulated with (S) or without (U) IFN-γ/LPS and subjected to intracellular staining for IL-12 and surface staining for CD3, CD19, or CD11c. (E) Representative dot plots showing IL-2 and IFN-γ production in CD4+ T cells treated with IL-12 (100 ng/ml) plus IL-2 (20 ng/ml) and IL-2 (20 ng/ml) alone at different time points (n = 3). Cells were incubated in anti-CD3–coated plates for the indicated times and then restimulated with PMA/ion in the presence of brefeldin A for 5 hours. Cytokine production was measured by intracellular staining. Percentages of total cell numbers are indicated in D and E. (F) Frequency of TH1 and TH17 cells in biopsy specimens from FL, hyperplastic LNs (HP), peripheral blood from healthy donors (PB), and benign tonsil tissue (Ton). TH1 and TH17 cells were measured by flow cytometry and defined as CD4+IFN-γ+ and CD4+IL-17+ cells, respectively. Horizontal error bars indicate median expression levels.

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