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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1271-1282
Number of pages12
JournalJournal of Clinical Investigation
Volume122
Issue number4
DOIs
StatePublished - Apr 2 2012

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B-Cell Lymphoma
Interleukin-12
Non-Hodgkin's Lymphoma
Up-Regulation
T-Lymphocytes
Mucins
Virus Diseases
Natural Killer Cells
Cell Differentiation
Immunity
Cell Proliferation
Clinical Trials
Cytokines

ASJC Scopus subject areas

  • Medicine(all)

Cite this

IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. / Yang, Zhi Zhang; Grote, Deanna M.; Ziesmer, Steven C.; Niki, Toshiro; Hirashima, Mitsuomi; Novak, Anne J; Witzig, Thomas Elmer; Ansell, Stephen Maxted.

In: Journal of Clinical Investigation, Vol. 122, No. 4, 02.04.2012, p. 1271-1282.

Research output: Contribution to journalArticle

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