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Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling

Authors
 Chen-Lu Geng  ;  Jun-Yi Chen  ;  Tian-Yu Song  ;  Jae Hyung Jung  ;  Min Long  ;  Min-Fang Song  ;  Tong Ji  ;  Byung Soh Min  ;  Jin Gu Lee  ;  Bo Peng  ;  Yi-Sheng Pu  ;  Hong-Jie Fan  ;  Piliang Hao  ;  Qi Zhou  ;  Eui-Cheol Shin  ;  Yong Cang 
Citation
 CELL CHEMICAL BIOLOGY, Vol.29(8) : 1260-1272, 2022-08 
Journal Title
CELL CHEMICAL BIOLOGY
ISSN
 2451-9456 
Issue Date
2022-08
MeSH
Animals ; CD28 Antigens* ; CD8-Positive T-Lymphocytes ; Immunologic Factors ; Immunotherapy / methods ; Lenalidomide / pharmacology ; Mice ; Programmed Cell Death 1 Receptor*
Keywords
CD28 ; CRBN ; Notch signaling ; PD-1 ; immunotherapy ; lenalidomide
Abstract
Programmed cell death protein 1 (PD-1) checkpoint blockade therapy requires the CD28 co-stimulatory receptor for CD8+ T cell expansion and cytotoxicity. However, CD28 expression is frequently lost in exhausted T cells and during immune senescence, limiting the clinical benefits of PD-1 immunotherapy in individuals with cancer. Here, using a cereblon knockin mouse model that regains in vivo T cell response to lenalidomide, an immunomodulatory imide drug, we show that lenalidomide reinstates the anti-tumor activity of CD28-deficient CD8+ T cells after PD-1 blockade. Lenalidomide redirects the CRL4Crbn ubiquitin ligase to degrade Ikzf1 and Ikzf3 in T cells and unleashes paracrine interleukin-2 (IL-2) and intracellular Notch signaling, which collectively bypass the CD28 requirement for activation of intratumoral CD8+ T cells and inhibition of tumor growth by PD-1 blockade. Our results suggest that PD-1 immunotherapy can benefit from a lenalidomide combination when treating solid tumors infiltrated with abundant CD28- T cells.
Full Text
https://www.sciencedirect.com/science/article/pii/S2451945622002045
DOI
10.1016/j.chembiol.2022.05.012
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Thoracic and Cardiovascular Surgery (흉부외과학교실) > 1. Journal Papers
Yonsei Authors
Min, Byung Soh(민병소) ORCID logo https://orcid.org/0000-0003-0180-8565
Lee, Jin Gu(이진구)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/193422
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