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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

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 4

Coexpression of TIM-3 and PD-1 in FL.

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Coexpression of TIM-3 and PD-1 in FL.
(A) Representative plots showing e...
(A) Representative plots showing expression of T-bet, RORγt, GATA-3, or Foxp3 in TIM-3– or TIM-3+ cells in CD4+ or CD8+ T cells in FL patients. Freshly isolated MCs were fixed, permeabilized, and stained for T-bet, RORγt, GATA-3, or Foxp3 plus TIM-3, CD3, CD4, and CD8. (B) Dot plots showing expression of PD-1 and TIM-3 on CD4+ or CD8+ T cells from a representative LN biopsy of FL patients (n = 10). (C) Correlation analysis for CD4+PD-1+ (left) or CD8+PD-1+ (right) T cells with CD4+ or CD8+TIM-3+ T cells in FL patients. The frequency of CD4+PD-1+, CD8+PD-1+, CD4+TIM-3+, or CD8+TIM-3+ T cells was measured by flow cytometry. Percentages of total cell numbers are indicated in A, B, and D. (D) Dot plots showing expression of PD-1 and CXCR5 on TIM-3–expressing CD4+ (upper panels) or CD8+ (lower panels) T cells from a representative LN biopsy of FL patient (n = 10).

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