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This UCSF preclinical study reaffirms IL-6 as an important regulator of the glioblastoma (GBM) immune tumor microenvironment (TME) and a potential target for combination therapy. Using integrated spatial and single-cell analyses of patient-matched human GBM samples, the authors show that lower baseline IL-6 is associated with the rare clinical responses seen with immune checkpoint inhibitors (ICIs), while higher IL-6 correlates with poorer outcomes. These findings are consistent with prior observations by Dr. Steven Brem and others linking IL-6 to glioma progression, senescence-associated genes, immune suppression and prognosis in GBM.
In the current study by Jacob Young, et al., using preclinical models, IL-6 blockade alone was not sufficient for durable tumor control, but it shifted the tumor immune microenvironment to a more immunoresponsive TME by reducing regulatory T cells, activating dendritic cells, and increasing antigen presentation and effector CD8+ T-cell activity. When combined with immune checkpoint inhibition and radiotherapy, IL-6 blockade translated into more durable anti-tumor responses. This work further supports a combination strategy of targeting cytokine-driven resistance pathways by blocking IL-6, and potentially other immunosuppressive cytokines, to overcome immunotherapy resistance in GBM. Currently, an NRG multicenter trial (NCT04729959), combining anti-IL6R antibody (tocilizumab) with an ICI (atezolizumab) and fractionated radiotherapy has completed accrual and the data is being analyzed. We will share those results when they become available!