title: IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma.
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.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. yang.zhizhang@mayo.edu
authors.forename: Zhi-Zhang
authors.initials: ZZ
authors.lastname: Yang
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Grote
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ziesmer
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niki
authors.forename: Mitsuomi
authors.initials: M
authors.lastname: Hirashima
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Novak
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000097:blood / Q000494:pharmacology* / Q000502:physiology; D053208:Kaplan-Meier Estimate; D008070:Lipopolysaccharides / Q000494:pharmacology; D008224:Lymphoma, Follicular / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D014157:Transcription Factors; D018664:Interleukin-12; D007371:Interferon-gamma