IL-8 in Human Glioblastoma Tumors Instructs Immunosuppressive Myeloid Cells

Adult glioblastoma (GBM) is an aggressive brain tumor that has yet to benefit from advances in immunotherapy. Prior studies report contrasting leukocyte immunophenotypes between tumors and an association between myeloid macrophage infiltration and worse patient outcomes. IL-8, a cytokine with both inflammatory and suppressive roles, was recently associated with M2 macrophage phenotypes in GBM. These observations raise key questions: do GBM macrophages suppress or support other immune cells, is IL-8 in GBM a mechanistic driver of GBM macrophage function, and can IL-8 instruct macrophages in situ within tumors? Here, functional experiments with primary human GBM tumor cells from initial surgical resections showed that IL-8 from GBM contributes to and is sufficient to instruct monocyte-derived macrophages that suppress healthy T cells. Notably, IL-8 protein expression was enriched in aggressive tumors contacting the V-SVZ region and was not associated with increased infiltration of cells expressing the IL-8 receptors CXCR1/CXCR2. Suppressor cells instructed by GBM ex vivo phenotypically matched myeloid macrophages observed in vivo, and neutralizing IL-8 during instruction blocked this and restored T cell proliferation. Analysis of IL-8 RNA showed the cytokine is primarily produced by CD45- tumor cells. These results suggest a model where ongoing IL-8 production by GBM cells maintains an immunosuppressive microenvironment by signaling to myeloid macrophages within the tumor. Immunotherapies relying on T cells should now investigate whether IL-8 blockade prevents instruction of macrophages into tumor-protective suppressor cells.