B6-h4-1BB/hPDL1 Mice

Catalog Number: C001686

Strain Name: C57BL/6N;6JCya-Tnfrsf9em1(hTNFRSF9)Cd274em1(hCD274)/Cya

Genetic Background: C57BL/6N;6JCya

Reproduction: Homozygous B6-h4-1BB(TNFRSF9) mice x Homozygous B6-hPDL1 mice

 

Strain Description

The TNFRSF9 gene, also known as 4-1BB/CD137, encodes a protein that belongs to the TNF receptor superfamily. This receptor aids in the clonal expansion, survival, and development of T cells. It can also induce the proliferation of peripheral monocytes, enhance TCR/CD3-triggered activation-induced T cell apoptosis, and regulate CD28 co-stimulation to promote Th1 cell responses. TRAF adaptor proteins can bind to it and transmit signals that activate NF-kappaB. Many immune cell types express TNFRSF9, including activated NK cells, NKT cells, B cells, eosinophils, basophils, mast cells, neutrophils, mature Tregs, activated monocytes, and dendritic cells. Additionally, TNFRSF9 may be expressed in non-immune cell types such as endothelial cells, neurons, astrocytes, and microglia. TNFRSF9 plays roles in innate and adaptive immunity, including cancer immunology and autoimmune diseases [1]. Due to its broad expression profile and immune response functions, 4-1BB is a potential target for cancer and immunotherapy. In recent years, research on second-generation 4-1BB agonists has been expanding, with various strategies being implemented to overcome the liver toxicity and efficacy limitations of the first generation [2-3].

Programmed cell death 1 ligand 1 (PD-L1), also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7H1), is an immune inhibitory receptor ligand. PD-L1 is a type I transmembrane protein with immunoglobulin V-like (IgV) and C-like (IgC) structural domains and is expressed by hematopoietic and non-hematopoietic cells, including T cells, B cells, and various types of tumor cells [4]. PD-L1 can bind to the PD-1 on the surface of CD8+ T cells, inhibiting the activity of CD8+ T cells. This interaction can prevent the immune system from damaging normal tissues, but it can also be used by tumor cells to escape immune surveillance. Monoclonal antibodies that competitively bind to PD-L1 can relieve the immune function inhibition mediated by the binding of PD-1 and PD-L1. This can reactivate CD8+ T cells, triggering the human body's anti-tumor immune response [5]. Therefore, developing of antibody drugs targeting PD-1 and PD-L1 is a hot area in tumor immunotherapy [5-7].

B6-h4-1BB/hPDL1 mice are TNFRSF9 and CD274 double humanized mouse models obtained by mating TNFRSF9 humanized mouse models (Catalog No. C001604) with CD274 humanized mouse models (Catalog No. C001235). They express human TNFRSF9 and CD274 genomic sequences under the control of mouse promoters. This model is a valuable tool for studying cancer immunotherapy. In addition, this model also provides a powerful preclinical research platform for evaluating the efficacy and mechanism of therapeutic drugs targeting TNFRSF9 and CD274.

 

Strain Strategy

  • Gene editing strategy of B6-h4-1BB(TNFRSF9) mice. The mouse Tnfrsf9 endogenous extracellular domain (aa.24~187) was replaced with the human TNFRSF9 extracellular domain (aa.24~186).



  • Gene editing strategy of B6-hPDL1 mice. Part of exon 2 coding sequence plus partial intron 2 of mouse CD274 gene will be replaced with the “Human CD274 CDS-Mouse Cd274 3’UTR-rBG pA” cassette.


Application

  • 4-1BB/PD-L1-targeted drug screening, development, and evaluation;
  • Research on the pathological mechanisms and therapeutic approaches of cancer immunotherapy.

 

References
[1]Eckstrum K, Bany BM. Tumor necrosis factor receptor subfamily 9 (Tnfrsf9) gene is expressed in distinct cell populations in mouse uterus and conceptus during implantation period of pregnancy. Cell Tissue Res. 2011 Jun;344(3):567-76.
[2]Kim AMJ, Nemeth MR, Lim SO. 4-1BB: A promising target for cancer immunotherapy. Front Oncol. 2022 Sep 14;12:968360.
[3]Claus C, Ferrara-Koller C, Klein C. The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy. MAbs. 2023 Jan-Dec;15(1):2167189.
[4] Kornepati AVR, Vadlamudi RK, Curiel TJ. Programmed death ligand 1 signals in cancer cells. Nat Rev Cancer. 2022 Mar;22(3):174-189.
[5] Escors D, Gato-Cañas M, Zuazo M, Arasanz H, García-Granda MJ, Vera R, Kochan G. The intracellular signalosome of PD-L1 in cancer cells. Signal Transduct Target Ther. 2018 Sep 28;3:26.
[6] Huang CY, Wang Y, Luo GY, Han F, Li YQ, Zhou ZG, Xu GL. Relationship Between PD-L1 Expression and CD8+ T-cell Immune Responses in Hepatocellular Carcinoma. J Immunother. 2017 Nov/Dec;40(9):323-333.
[7] Zhang C, Wu S, Xue X, Li M, Qin X, Li W, Han W, Zhang Y. Anti-tumor immunotherapy by blockade of the PD-1/PD-L1 pathway with recombinant human PD-1-IgV. Cytotherapy. 2008;10(7):711-9.