Abstract 2000: Systemic and tumor associated IL-8 correlates with resistance to PD-L1 blockade

Elevated plasma interleukin-8 (IL-8) is a poor prognostic factor for many cancers. However, the association of IL-8 with clinical outcomes to checkpoint inhibition has not been comprehensively evaluated in randomized studies. Moreover, the source of IL-8 and the underlying biology that influences resistance to immune checkpoint inhibitors remain unknown. Here we analyzed circulating IL-8 protein in plasma, and IL8 gene expression in peripheral blood mononuclear cells (PBMC) and tumors of patients treated with atezolizumab (anti-PD-L1 mAb), from multiple randomized trials in metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma (mRCC). High levels of IL-8 in plasma, PBMCs and tumors, were associated with decreased efficacy in mUC and mRCC patients treated with atezolizumab, even in tumors that were classically CD8+ T cell inflamed. mUC patients treated with atezolizumab, but not with chemotherapy, who experienced an on-treatment decrease in plasma IL-8, exhibited improved overall survival. IL-8 is primarily expressed in circulating and intratumoral myeloid cells, and high IL8 expression was associated with the downregulation of the antigen presentation machinery in myeloid cells. A better understanding of IL-8-mediated myeloid inflammation in curtailing responses to checkpoint inhibitors is essential for developing new therapies for patients. Citation Format: Kobe Yuen, Lifen Liu, Congfen Li, Deepali Rishipathak, Patrick Williams, Edward Kadel, Hartmut Koeppen, Shravan Madireddi, Shilpa Keerthivasan, Ying-Jun Chen, Zora Modrusen, Romain Banchereau, Ning Leng, Priti Hegde, Mahrukh Huseni, Sanjeev Mariathasan. Systemic and tumor associated IL-8 correlates with resistance to PD-L1 blockade [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2000.