Neutralizing IL-8 potentiates immune checkpoint blockade efficacy for glioma

Malignant gliomas are largely refractory to immune checkpoint blockade (ICB) therapy. To explore the under-lying immune regulators, we examine the microenvironment in glioma and find that tumor-infiltrating T cells are mainly confined to the perivascular cuffs and express high levels of CCR5, CXCR3, and programmed cell death protein 1 (PD-1). Combined analysis of T cell clustering with T cell receptor (TCR) clone expansion shows that potential tumor-killing T cells are mainly categorized into pre-exhausted/exhausted and effector CD8+ T subsets, as well as cytotoxic CD4+ T subsets. Notably, a distinct subpopulation of CD4+ T cells ex-hibits innate-like features with preferential interleukin-8 (IL-8) expression. With IL-8-humanized mouse strain, we demonstrate that IL-8-producing CD4+ T, myeloid, and tumor cells orchestrate myeloid-derived suppres-sor cell infiltration and angiogenesis, which results in enhanced tumor growth but reduced ICB efficacy. Antibody-mediated IL-8 blockade or the inhibition of its receptor, CXCR1/2, unleashes anti-PD-1-mediated antitumor immunity. Our findings thus highlight IL-8 as a combinational immunotherapy target for glioma.

Automated summary

By examining the microenvironment in glioma, we find that tumor-infiltrating T cells are mainly located in the perivascular cuffs and express high levels of CCR5, CXCR3, and PD-1. Analysis of T cell clustering and TCR clone expansion reveals that potential tumor-killing T cells belong to pre-exhausted/exhausted and effector CD8+ T subsets, as well as cytotoxic CD4+ T subsets. In addition, a distinctive subpopulation of CD4+ T cells with innate-like features and preferential interleukin-8 (IL-8) expression is identified. We demonstrate that IL-8, along with myeloid and tumor cells, coordinates myeloid-derived suppressor cell infiltration and angiogenesis, leading to enhanced tumor growth but reduced efficacy of immune checkpoint blockade therapy. Blockade of IL-8 or its receptor CXCR1/2 unleashes the antitumor immunity mediated by anti-PD-1. Therefore, IL-8 is highlighted as a potential immunotherapy target for glioma.