2. Academic Validation
  3. TIGIT immune checkpoint blockade enhances immunity of human peripheral blood NK cells against castration-resistant prostate cancer

TIGIT immune checkpoint blockade enhances immunity of human peripheral blood NK cells against castration-resistant prostate cancer

  • Cancer Lett. 2023 Jul 4;568:216300. doi: 10.1016/j.canlet.2023.216300.
Fangming Wang 1,  Shuai Liu 2,  Fei Liu 3,  Tianli Xu 2,  Jianlin Ma 2,  Jing Liang 4,  Jing Wang 2,  Donghua Liu 2,  Feiya Yang 3,  Jianxing Li 5,  Nianzeng Xing 6
Affiliations

Affiliations

  • 1 Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China; Department of Urology, Tsinghua University Affiliated Beijing Tsinghua Changgung Hospital, Tsinghua University Clinical Institute, 102218, Beijing, China.
  • 2 BOE Regenerative Medicine Technology Co. Ltd., 100015, Beijing, China.
  • 3 Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
  • 4 Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
  • 5 Department of Urology, Tsinghua University Affiliated Beijing Tsinghua Changgung Hospital, Tsinghua University Clinical Institute, 102218, Beijing, China. Electronic address: ljxa01048@btch.edu.cn.
  • 6 Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China; State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China. Electronic address: xingnz@cicams.ac.cn.
PMID: 37414394 DOI: 10.1016/j.canlet.2023.216300
Abstract

Castration-resistant prostate Cancer (CRPC) patients have a 14-month median survival, emphasizing the need for alternative treatments. Previously, we demonstrated that expanded high-dose natural killer (NK) cells derived from human peripheral blood exhibit therapeutic efficacy against CRPC. However, which Immune Checkpoint blockade promotes NK cell antitumor immunity against CRPC remains unknown. Here, we explored Immune Checkpoint molecule expression in NK and CRPC cells during their interactions, and identified that the T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) monoclonal antibody (mAb), vibostolimab, significantly enhanced NK cell cytotoxicity against CRPC cells and cytokine production in vitro, demonstrated by upregulation of degranulation marker CD107a and Fas-ligand (Fas-L) and increased interferon-gamma (IFN-γ) and tumor necrosis factor-alpha secretion. TIGIT blockade increased Fas-L expression and IFN-γ production via the NF-κB signaling pathway and restored degranulation via the mitogen-activated protein kinase ERK (extracellular signal-regulated kinase) kinase/ERK pathway in activated NK cells. Vibostolimab significantly enhanced NK cell antitumor effects against CRPC in two xenograft mouse models. Vibostolimab also increased T cell chemotaxis induced by activated NK cells in vitro and in vivo. Overall, blocking TIGIT/CD155 signaling enhances the antitumor effect of expanded NK cells against CRPC; this finding supports the translational application of TIGIT mAb and NK cell combination strategies from bench to bedside for CRPC treatment.

Keywords

CD107a; CD155; Fas-L; IFN-γ; Vibostolimab.

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