High systemic and tumor-associated IL8 correlates with reduced clinical benefit of PD-L1 blockade

Although elevated plasma interleukin-8 (pIL8) has been associated with poor outcome to immune checkpoint blockade (ICB), 1 this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL8, and IL8 gene expression in peripheral blood mononuclear cells (PBMCs) and tumors of patients treated with atezolizumab (anti-PD-L1 mAb) from multiple randomized trials representing 1445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma (mRCC). High levels of IL8 in plasma, PBMCs, and tumors were associated with decreased efficacy of atezolizumab in mUC and mRCC patients, even in tumors that were classically CD8+ T cell inflamed. Low baseline pIL8 in mUC patients was associated with increased response to atezolizumab and chemotherapy. mUC patients who experienced on-treatment decrease in pIL8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNASeq (scRNAseq) of the immune compartment showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and that high IL8 expression is associated with downregulation of the antigen presentation machinery. Therapies that can reverse the impacts of IL8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.