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

被引：104

作者：

Huseni, Mahrukh A. ^{[1
]}

Wang, Lifen ^{[1
]}

Klementowicz, Joanna E. ^{[1
]}

Yuen, Kobe ^{[1
]}

Breart, Beatrice ^{[1
]}

Orr, Christine ^{[1
]}

Liu, Li-fen ^{[1
]}

Li, Yijin ^{[1
]}

Gupta, Vinita ^{[1
]}

Li, Congfen ^{[1
]}

Rishipathak, Deepali ^{[1
]}

Peng, Jing ^{[1
]}

Senbabaoglu, Yasin ^{[1
]}

Modrusan, Zora ^{[1
]}

Keerthivasan, Shilpa ^{[1
]}

Madireddi, Shravan ^{[1
]}

Chen, Ying-Jiun ^{[1
]}

Fraser, Eleanor J. ^{[1
]}

Leng, Ning ^{[1
]}

Hamidi, Habib ^{[1
]}

Koeppen, Hartmut ^{[1
]}

Ziai, James ^{[1
]}

Hashimoto, Kenji ^{[1
]}

Fasso, Marcella ^{[1
]}

Williams, Patrick ^{[1
]}

McDermott, David F. ^{[2
]}

Rosenberg, Jonathan E. ^{[3
]}

Powles, Thomas ^{[4
]}

Emens, Leisha A. ^{[5
]}

Hegde, Priti S. ^{[1
]}

Mellman, Ira ^{[1
]}

Turley, Shannon J. ^{[1
]}

Wilson, Mark S. ^{[1
]}

Mariathasan, Sanjeev ^{[1
]}

Molinero, Luciana ^{[1
]}

Merchant, Mark ^{[1
]}

West, Nathaniel R. ^{[1
]}

机构：

[1] Genentech Inc, San Francisco, CA 94080 USA

[2] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA

[3] Mem Sloan Kettering Canc Ctr, Dept Med, Genitourinary Oncol Serv, New York, NY 10065 USA

[4] Queen Mary Univ London, Barts Canc Inst, Barts Expt Canc Med Ctr, London EC1M 6BQ, England

[5] Univ Pittsburgh, Hillman Canc Ctr, Med Ctr, Pittsburgh, PA 15213 USA

来源：

CELL REPORTS MEDICINE | 2023年 / 4卷 / 01期

关键词：

CD8(+) T-CELLS; METASTATIC UROTHELIAL CARCINOMA; SUPPRESSOR-CELLS; PD-L1; BLOCKADE; DIFFERENTIATION; EFFECTOR; EXPRESSION; STAT3; BET; ATEZOLIZUMAB;

D O I：

10.1016/j.xcrm.2022.100878

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming ther-apeutic 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 can-cers. 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 defi-ciency 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.

引用

页数：21

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