Spotlights
SEMINAR: Dr. Michael T. Lotze

Speaker: Michael T. Lotze

Topic:     HMGB1 in Immune Cells Regulates Immunity.

Time:      14:00-15:30PM, March. 22th (Thursday)

Venue:    D326, Medical Science Building

Host:       Dr. Yan Shi

Abstract

HMGB1 is the prototypical DAMP, playing a critical role in immunobiology. To investigate the role of DC HMGB1 in tumor immunity, CD11c+-specific HMGB1-/- mice (DCH) were generated. HMGB1-/- knockout in DCs limited their maturation and chemotaxis (p = 0.001). In subcutaneous and liver metastasis cancer models, tumors grew substantially less in DCH mice (p < 0.05 and 0.01, respectively). Transplantation of DCH bone marrow limited development of PanIN lesions and associated inflammatory infiltrate in animals expressing oncogenic pancreatic KrasG12D (p = 0.0317). Mice challenged with tumors and vaccinated with DCH DCs pulsed with tumor antigen provided no protection compared to WT controls (p < 0.05). DCH animals had responses skewed away from Th1/Th2 phenotypes, promoting Treg/Th17 polarization as measured by cytokine release. They were also less responsive to TLR agonists. Our findings suggest a new and critical role for tumor associated DCs, enhancing tumor growth and persistence through an HMGB1 dependent process. Natural Killer cells (NK cells) are critical effectors in innate immunity, especially in tumor and virus surveillance. We also generated NKp46+ specific HMGB1 knockout mice (NKH mice), characterized the phenotype and functions of NK cell lacking HMGB1 in vivo and in vitro. We observed tumors engrafted more readily in NKH mice (p <0.0001), but then grew at a comparable rate as tumors in wild-type (WT) mice, suggesting NK cells are crucial in early tumor surveillance in an HMGB1-dependent manner. NKH mice thus died from tumor progression much earlier than WT animals (p=0.0036). Ex vivo cytotoxicity was dramatically reduced in tumor-bearing NKH mice (p<0.001), consistent with diminished in vitro lytic capacity. Ablation of HMGB1 impaired NK cells ability to secrete IFN-γ and induce DC maturation. Addition of exogenous HMGB1 restored this capacity Reserve capacities of both OXPHOS and glycolysis decreased with HMGB1 deficiency (p<0.001), as did ATP production. NKH cells with HMGB1 ablation had defects in autophagy regulation, which may be a central explanation for many of the defective phenotypes observed in NKH cells. Consistently, inhibition of autophagy impaired function of NK cells, perhaps reflecting a role of the autophagic machinery in NK vesicular exocytosis. Endogenous HMGB1 NK cell facilitates diverse NK functions, modulating autophagy and regulating bioenergetics. Studies conducted using IL-2 based immunotherapy in RAG-/-mice, demonstrated that lethality could be blocked by eliminating NK cells or ablating NK HMGB1 expression. A recently conducted clinical trial in patients with renal carcinoma with IL-2 and the autophagy inhibitor, hydroxychloroquine (HCQ) was associated with diminished HMGB1 in the serum compared to individuals without HCQ and comparable antitumor responses (3CR/30 treated patients).

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