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.
Highlights
Immunologically-cold tumors including glioblastoma (GBM) are refractory to checkpoint blockade therapy, largely due to extensive infiltration of immunosuppressive macrophages (Mφs)
We investigated the role of IL-6 for tumor immunosuppression in GBM, initially using a genetic approach (Fig. 1a)
GBM was induced in Ntv-a; Ink4a-Arf−/−;Ptenfl/fl;LSL-Luc donor mice by RCAS-mediated gene transfer, followed by orthotopic implantation of tumor cells into Cdh5-CreERT2;Il6fl/fl mice, in which IL-6 expression is controlled by endothelial cells (ECs)-specific promoter Cdh[5]
Summary
Immunologically-cold tumors including glioblastoma (GBM) are refractory to checkpoint blockade therapy, largely due to extensive infiltration of immunosuppressive macrophages (Mφs). Current immunotherapy approaches against solid tumors remain a significant challenge, in particular for immunologically cold tumors, i.e., those characterized with low T-cell infiltrates, including glioblastoma (GBM)[1,2,3,4,5,6] In these tumors, the therapeutic difficulties and failures are largely due to an immune-hostile, suppressive tumor microenvironment that abrogates T-cell infiltration and activation. Based on our transcriptome analysis that identifies an IL-6-inducible mechanism for Mφ activation via Stat3/HIF-1α/CD40, we develop a dual-targeting anti-IL-6 and pro-CD40 strategy, which may offer exciting opportunities for activating Mφ immunity and improving T-cell-based immunotherapy in solid tumors
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