Synergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40

Fan Yang, Zhenqiang He, Hao Duan, Duo Zhang, Juehui Li, Huijuan Yang, Jay F. Dorsey, Wei Zou, S. Ali Nabavizadeh, Stephen J. Bagley, Kalil Abdullah, Steven Brem, Lin Zhang, Xiaowei Xu, Katelyn T. Byrne, Robert H. Vonderheide (), Yanqing Gong () and Yi Fan ()
Additional contact information
Fan Yang: University of Pennsylvania
Zhenqiang He: University of Pennsylvania
Hao Duan: University of Pennsylvania
Duo Zhang: University of Pennsylvania
Juehui Li: University of Pennsylvania
Huijuan Yang: University of Pennsylvania
Jay F. Dorsey: University of Pennsylvania
Wei Zou: University of Pennsylvania
S. Ali Nabavizadeh: University of Pennsylvania
Stephen J. Bagley: University of Pennsylvania
Kalil Abdullah: University of Pennsylvania
Steven Brem: University of Pennsylvania
Lin Zhang: University of Pennsylvania
Xiaowei Xu: University of Pennsylvania
Katelyn T. Byrne: University of Pennsylvania
Robert H. Vonderheide: University of Pennsylvania
Yanqing Gong: University of Pennsylvania
Yi Fan: University of Pennsylvania

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23832-3

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