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

Cell Rep Med. 2023 Jan 17;4(1):100878. doi: 10.1016/j.xcrm.2022.100878. Epub 2023 Jan 3.


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.

Keywords: CD8 T cell; IL-6; PD-L1; atezolizumab; cancer; checkpoint blockade immunotherapy; clinical trial; interleukin 6.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents* / therapeutic use
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / therapeutic use
  • CD8-Positive T-Lymphocytes / metabolism
  • Immunotherapy
  • Interleukin-6* / metabolism
  • Mice
  • Neoplasms* / immunology
  • Neoplasms* / therapy


  • Antineoplastic Agents
  • atezolizumab
  • B7-H1 Antigen
  • Interleukin-6