CD8(+) T cell-intrinsic IL-6 signaling promotes resistance to anti-PD-L1 immunotherapy Journal Article
| Authors: | Huseni, M. A.; Wang, L.; Klementowicz, J. E.; Yuen, K.; Breart, B.; Orr, C.; Liu, L. F.; Li, Y.; Gupta, V.; Li, C.; Rishipathak, D.; Peng, J.; Şenbabaoǧlu, Y.; Modrusan, Z.; Keerthivasan, S.; Madireddi, S.; Chen, Y. J.; Fraser, E. J.; Leng, N.; Hamidi, H.; Koeppen, H.; Ziai, J.; Hashimoto, K.; Fassò, M.; Williams, P.; McDermott, D. F.; Rosenberg, J. E.; Powles, T.; Emens, L. A.; Hegde, P. S.; Mellman, I.; Turley, S. J.; Wilson, M. S.; Mariathasan, S.; Molinero, L.; Merchant, M.; West, N. R. |
| Article Title: | CD8(+) T cell-intrinsic IL-6 signaling promotes resistance to anti-PD-L1 immunotherapy |
| Abstract: | 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. © 2022 The Author(s) |
| Keywords: | clinical trial; interleukin 6; cd8 t cell; pd-l1; il-6; cancer; atezolizumab; checkpoint blockade immunotherapy |
| Journal Title: | Cell Reports Medicine |
| Volume: | 4 |
| Issue: | 1 |
| ISSN: | 2666-3791 |
| Publisher: | Cell Press |
| Date Published: | 2023-01-17 |
| Start Page: | 100878 |
| Language: | English |
| DOI: | 10.1016/j.xcrm.2022.100878 |
| PUBMED: | 36599350 |
| PROVIDER: | scopus |
| PMCID: | PMC9873827 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 February 2023 -- Source: Scopus |
