2. Academic Validation
  3. Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling

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

  • Cell Chem Biol. 2022 Aug 18;29(8):1260-1272.e8. doi: 10.1016/j.chembiol.2022.05.012.
Chen-Lu Geng 1,  Jun-Yi Chen 2,  Tian-Yu Song 3,  Jae Hyung Jung 4,  Min Long 1,  Min-Fang Song 2,  Tong Ji 5,  Byung Soh Min 6,  Jin Gu Lee 7,  Bo Peng 2,  Yi-Sheng Pu 2,  Hong-Jie Fan 2,  Piliang Hao 2,  Qi Zhou 8,  Eui-Cheol Shin 4,  Yong Cang 9
Affiliations

Affiliations

  • 1 Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China; School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China.
  • 3 School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China; Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 4 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
  • 5 Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 6 Department of Surgery, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 7 Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 8 Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.
  • 9 School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China. Electronic address: [email protected].
PMID: 35732177 DOI: 10.1016/j.chembiol.2022.05.012
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.

Keywords

CD28; CRBN; Notch signaling; PD-1; immunotherapy; lenalidomide.

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