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Glioblastoma (GBM) is refractory to current T cell-based immunotherapies such as checkpoint blockade. GBM is characterized by extensive infiltration of immunosuppressive macrophages (Mφs) that contribute to the treatment resistance. Here we develop a dual-targeting strategy to synergistically activate tumor-associated Mφs, which overcomes GBM resistance to therapeutic blockade of the PD1 and CTLA4 checkpoints. Consistent with a previously established role of IL-6 in alternative Mφ polarization, we show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T cell infiltration and enhances animal survival in a genetically engineered mouse GBM model. However, IL-6 inhibition does not synergize PD-1 and CTLA-4 blockade in GBM. Interestingly, we reveal that anti-IL-6 therapy reduces CD40 expression in GBM-associated Mφs. Our transcriptome analysis identifies a Stat3/HIF-1a-mediated axis, through which IL-6 regulates CD40 expression in Mφs. Finally, we show that combination of IL-6 blockade with CD40 stimulation robustly reverses Mφ-mediated tumor immunosuppression, enhances T cell infiltration, and sensitizes GBM to PD-1 and CTLA-4 blockade treatment, cumulating in inhibited tumor growth and extended animal survival. These findings illustrate a cellular mechanism that regulates Mφ-mediated tumor immunity, and suggest that dual-targeting IL-6 and CD40 may offer exciting opportunities for improving immunotherapy against GBM.

IMMU-11. DUAL TARGETING OF IL-6 AND CD40 OVERCOMES GLIOBLASTOMA RESISTANCE TO IMMUNE CHECKPOINT BLOCKADE