N-cadherin inhibitor creates a microenvironment that protect TILs from immune checkpoints and Treg cells

Autor: Jun Jing, Yi Sun, Qiang Wei, Lu Yang, Huan Xu, Lingfan Xu, Hailiang Hu, Cai Tang, Shengzhuo Liu, Ruiqi Duan, Ju Guo
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Journal for ImmunoTherapy of Cancer, Vol 9, Iss 3 (2021)
Druh dokumentu: article
ISSN: 2020-0021
2051-1426
DOI: 10.1136/jitc-2020-002138
Popis: Background Few patients with prostate cancer benefit from current immunotherapies. Therefore, we aimed to explore new strategies to change this paradigm.Methods Human tissues, cell lines and in vivo experiments were used to determine whether and how N-cadherin impacts the production of programmed death ligand-1 (PD-L1) and indole amine 2,3-dioxygenase (IDO-1) and whether N-cadherin can increase the production of effector (e)Treg cells. Then, we used PC3-bearing humanized non-obese diabetic/severe combined immunodeficiency IL2Rγnull (hNSG) mice with an intravenous injection of human CD34+ hematopoietic stem cells into the tail vein to evaluate whether the N-cadherin antagonist N-Ac-CHAVC-NH2 (designated ADH-1) could improve the therapeutic effect of tumor-infiltrating lymphocyte (TIL)-related treatment.Results N-cadherin dramatically upregulated the expression of PD-L1 and IDO-1 through IFN-γ (interferongamma) signaling and increasing the production of free fatty acids that could promote the generation of eTreg cells. In preclinical experiments, immune reconstitution mediated by TILs slowed tumor growth and extended the survival time; however, this effect disappeared after immune system suppression by PD-L1, IDO-1 and eTreg cells. Furthermore, ADH-1 effectively reduced immunosuppression and enhanced TIL-related therapy.Conclusions These data show that the N-cadherin antagonist ADH-1 promotes TIL antitumor responses. This important hurdle must be overcome for tumors to respond to immunotherapy.
Databáze: Directory of Open Access Journals
Externí odkaz: