High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade Research Letter
| Authors: | Yuen, K. C.; Liu, L. F.; Gupta, V.; Madireddi, S.; Keerthivasan, S.; Li, C.; Rishipathak, D.; Williams, P.; Kadel, E. E. 3rd; Koeppen, H.; Chen, Y. J.; Modrusan, Z.; Grogan, J. L.; Banchereau, R.; Leng, N.; Thastrom, A. C.; Shen, X.; Hashimoto, K.; Tayama, D.; van der Heijden, M. S.; Rosenberg, J. E.; McDermott, D. F.; Powles, T.; Hegde, P. S.; Huseni, M. A.; Mariathasan, S. |
| Title: | High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade |
| Abstract: | Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade1, 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+ 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. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. |
| Keywords: | cancer chemotherapy; controlled study; human tissue; treatment response; human cell; major clinical study; overall survival; bevacizumab; sunitinib; drug efficacy; cancer patient; cd8+ t lymphocyte; protein blood level; cancer immunotherapy; metastasis; gene expression; interleukin 8; antigen presentation; down regulation; bone marrow cell; taxane derivative; transitional cell carcinoma; kidney metastasis; peripheral blood mononuclear cell; vinflunine; randomized controlled trial (topic); phase 2 clinical trial (topic); phase 3 clinical trial (topic); human; priority journal; article; atezolizumab; single cell rna seq |
| Journal Title: | Nature Medicine |
| Volume: | 26 |
| Issue: | 5 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2020-05-01 |
| Start Page: | 693 |
| End Page: | 698 |
| Language: | English |
| DOI: | 10.1038/s41591-020-0860-1 |
| PUBMED: | 32405063 |
| PROVIDER: | scopus |
| PMCID: | PMC8286544 |
| DOI/URL: | |
| Notes: | Article -- Erratum issued, see DOI: 10.1038/s41591-021-01246-4 -- Export Date: 1 June 2020 -- Source: Scopus |
