Immune-mediated brain tumor regression requires HMGB1 release and subsequent TLR2 activation on tumor infiltrating dendritic cells

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Glioblastoma multiforme is the most common subtype of brain cancer, accounting for 25% of newly diagnosed tumors. Current treatments fail to significantly improve survival and patients diagnosed with GBM have a life expectancy of about 1 year. Immunotherapy is an attractive treatment modality for GBM which could be used in combination with conventional therapies. However, the immune mechanisms responsible for overcoming brain immune privilege and elicit specific anti-GBM T cells’ clonal expansion are not fully understood. Here we uncovered a novel pathway for the activation of GBM antigen-specific T-cell dependent immune response which is mediated by the release of the high-mobility-group box 1 (HMGB1) by dying tumor cells after treatment with TK (+GCV) and this can induce TLR2 signaling in dendritic cells (DC). Infiltration of bone marrow derived DC into GBM after the intratumoral expression of Flt3L and TK is dependent on TLR2 activation by endogenous ligands. Moreover, in the absence of TLR2 signaling, tumor infiltrating DC do not induce tumor antigen specific T cell proliferation. Blocking HMGB1 activity in vivo using glycyrrhizin or HMGB1 depleting antibodies and blocking TLR2 activity with TLR2-/- knockout mice completely inhibited Flt3L/TK induced brain tumor regression. These results indicate that endogenous TLR2 signaling induced by HMGB1 promotes CD8+ T cell dependent anti-GBM immune responses that result in tumor regression in vivo. Our results also point to the possibility that HMGB1 might be useful as a novel adjuvant therapy to overcome immunological privilege in the brain.
 Supported by NIH/NINDS: 1R01 NS44556.01, NS445561.01; 1R21-NSO54143.01; 1UO1 NS052465.01, 1 RO3 TW006273-01 to MGC. NIH/NINDS: 1 RO1 NS 054193.01; RO1 NS 42893.01, U54 NS045309-01 and 1R21 NS047298-01 to PRL. NIH/NINDS 1F32 NS058156.01 to MC.