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. [Display omitted] •High IL-6 associates with poor atezolizumab efficacy in patients with advanced cancer•IL6R- and PD-L1-blocking antibodies combine synergistically to treat murine tumors•IL-6-STAT3 signaling blocks cytotoxic effector differentiation of CD8+ T cells•Cell-intrinsic IL-6 signaling in CD8+ T cells limits pre-clinical anti-PD-L1 activity Identifying clinically actionable drivers of therapeutic resistance is a major objective for cancer immunotherapy. Here, Huseni et al. identify IL-6 as a correlate of poor clinical response to atezolizumab (anti-PD-L1) therapy and demonstrate that IL-6 impairs anti-PD-L1 efficacy by restricting the anti-tumor functions of cytotoxic T cells.