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Yang, Fan; He, Zhenqiang; Duan, Hao; Zhang, Duo; Li, Juehui; Yang, Huijuan; Dorsey, Jay F; Zou, Wei; Nabavizadeh, S Ali; Bagley, Stephen J; Abdullah, Kalil; Brem, Steven; Zhang, Lin; Xu, Xiaowei; Byrne, Katelyn T; Vonderheide, Robert H; Gong, Yanqing; Fan, Yi
Nature communications, 06/2021, Volume: 12, Issue: 1Journal Article
Immunologically-cold tumors including glioblastoma (GBM) are refractory to checkpoint blockade therapy, largely due to extensive infiltration of immunosuppressive macrophages (Mϕs). Consistent with a pro-tumor role of IL-6 in alternative Mϕs polarization, we here show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T-cell infiltration into GBM and enhances mouse survival; however, IL-6 inhibition does not synergize PD-1 and CTLA-4 checkpoint blockade. Interestingly, anti-IL-6 therapy reduces CD40 expression in GBM-associated Mϕs. We identify a Stat3/HIF-1α-mediated axis, through which IL-6 executes an anti-tumor role to induce CD40 expression in Mϕs. Combination of IL-6 inhibition with CD40 stimulation reverses Mϕ-mediated tumor immunosuppression, sensitizes tumors to checkpoint blockade, and extends animal survival in two syngeneic GBM models, particularly inducing complete regression of GL261 tumors after checkpoint blockade. Thus, antibody cocktail-based immunotherapy that combines checkpoint blockade with dual-targeting of IL-6 and CD40 may offer exciting opportunities for GBM and other solid tumors.
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