CD8+ T cell-intrinsic IL-6 signaling promotes resistance to anti-PD-L1 immunotherapy.

Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8+ cytotoxic T lymphocyte (CTL) responses compared with anti-PD-L1 alone. Circulating CTLs from cancer patients with high plasma IL-6 display a repressed functional profile based on single-cell RNA sequencing, and IL-6-STAT3 signaling inhibits classical cytotoxic differentiation of CTLs in vitro. In tumor-bearing mice, CTL-specific IL6R deficiency is sufficient to improve anti-PD-L1 activity. Thus, based on both clinical and experimental evidence, agents targeting IL-6 signaling are plausible partners for combination with ICIs in cancer patients.

Cell reports. Medicine. 2022 Dec 22 [Epub ahead of print]

Mahrukh A Huseni, Lifen Wang, Joanna E Klementowicz, Kobe Yuen, Beatrice Breart, Christine Orr, Li-Fen Liu, Yijin Li, Vinita Gupta, Congfen Li, Deepali Rishipathak, Jing Peng, Yasin Şenbabaoǧlu, Zora Modrusan, Shilpa Keerthivasan, Shravan Madireddi, Ying-Jiun Chen, Eleanor J Fraser, Ning Leng, Habib Hamidi, Hartmut Koeppen, James Ziai, Kenji Hashimoto, Marcella Fassò, Patrick Williams, David F McDermott, Jonathan E Rosenberg, Thomas Powles, Leisha A Emens, Priti S Hegde, Ira Mellman, Shannon J Turley, Mark S Wilson, Sanjeev Mariathasan, Luciana Molinero, Mark Merchant, Nathaniel R West

Genentech, South San Francisco, CA 94080, USA. Electronic address: ., Genentech, South San Francisco, CA 94080, USA., Beth Israel Deaconess Medical Center, Boston, MA 02215, USA., Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK., University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15213, USA., Genentech, South San Francisco, CA 94080, USA. Electronic address: .