1. High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade
- Author
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Yuen, Kobe C., Liu, Li-Fen, Gupta, Vinita, Madireddi, Shravan, Keerthivasan, Shilpa, Li, Congfen, Rishipathak, Deepali, Williams, Patrick, Kadel, Edward E., III, Koeppen, Harmut, Chen, Ying-Jiun, Modrusan, Zora, Grogan, Jane L., Banchereau, Romain, Leng, Ning, Thastrom, Ann Christine, Shen, Xiadong, Hashimoto, Kenji, Tayama, Darren, van der Heijden, Michiel S., Rosenberg, Jonathan E., McDermott, David F., Powles, Thomas, Hegde, Priti S., Huseni, Mahrukh A., and Mariathasan, Sanjeev more...
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Drug therapy ,Patient outcomes ,Health aspects ,Interleukin-8 -- Health aspects ,Bladder cancer -- Drug therapy -- Patient outcomes ,Apoptotic proteins -- Health aspects ,Monoclonal antibodies -- Patient outcomes -- Health aspects ,Renal cell carcinoma -- Drug therapy -- Patient outcomes ,Cancer metastasis -- Drug therapy -- Patient outcomes ,Metastasis -- Drug therapy -- Patient outcomes ,Carcinoma, Renal cell -- Drug therapy -- Patient outcomes - Abstract
Author(s): Kobe C. Yuen [sup.1] , Li-Fen Liu [sup.1] , Vinita Gupta [sup.1] , Shravan Madireddi [sup.1] , Shilpa Keerthivasan [sup.1] , Congfen Li [sup.1] , Deepali Rishipathak [sup.1] , [...], Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade.sup.1, this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and IL8 gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8.sup.+ T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing 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 IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors. In a retrospective analysis of data from three clinical trials, increased baseline peripheral and tumor IL-8 levels were associated with worse clinical outcomes in patients with metastatic urothelial carcinoma and metastatic renal cell carcinoma treated with anti-PD-L1 therapy. more...
- Published
- 2020
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