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,…

• A
  Amgen
• BS
  Bristol-Myers Squibb
• EL
  Eli Lilly and Company
• A
  AstraZeneca
• S
  Sanofi
• C
  Celgene
• AB
  Array BioPharma
• SP
  Syndax Pharmaceuticals
• M
  MacroGenics
• I
  Ipsen
• G
  Genentech
• CP
  Chugai Pharmaceutical