Mendoza Christopher, Mizrachi Dario
Department of Cell Biology and Physiology, College of Life Sciences, Brigham Young University, Provo, UT 84602, USA.
Biomedicines. 2022 Feb 4;10(2):381. doi: 10.3390/biomedicines10020381.
Decades of evidence suggest that alterations in the adhesion properties of neoplastic cells endow them with an invasive and migratory phenotype. Tight junctions (TJs) are present in endothelial and epithelial cells. Tumors arise from such tissues, thus, the role of TJ proteins in the tumor microenvironment is highly relevant. In the TJ, junctional adhesion molecules (JAM) play a key role in assembly of the TJ and control of cell-cell adhesion. Reprogramming of immune cells using chimeric antigen receptors (CAR) to allow for target recognition and eradication of tumors is an FDA approved therapy. The best-studied CAR-T cells recognize CD19, a B-cell surface molecule. CD19 is not a unique marker for tumors, liquid or solid. To address this limitation, we developed a biologic containing three domains: (1) pH-low-insertion peptide (pHLIP), which recognizes the low pH of the cancer cells, leading to the insertion of the peptide into the plasma membrane. (2) An extracellular domain of JAM proteins that fosters cell-cell interactions. (3) CD19 to be targeted by CAR-T cells. Our modular design only targets cancer cells and when coupled with anti-CD19 CAR-T cells, it decreases proliferation and metastasis in at least two cancer cell lines.
数十年的证据表明，肿瘤细胞黏附特性的改变使其具有侵袭性和迁移性表型。紧密连接（TJ）存在于内皮细胞和上皮细胞中。肿瘤起源于此类组织，因此，TJ蛋白在肿瘤微环境中的作用高度相关。在紧密连接中，连接黏附分子（JAM）在紧密连接的组装和细胞间黏附的控制中起关键作用。使用嵌合抗原受体（CAR）对免疫细胞进行重编程以实现肿瘤的靶向识别和根除是一种获得美国食品药品监督管理局（FDA）批准的疗法。研究最深入的CAR-T细胞可识别B细胞表面分子CD19。CD19并非液体或实体肿瘤的唯一标志物。为解决这一局限性，我们开发了一种包含三个结构域的生物制剂：（1）pH低插入肽（pHLIP），它可识别癌细胞的低pH值，导致该肽插入质膜。（2）促进细胞间相互作用的JAM蛋白的细胞外结构域。（3）可被CAR-T细胞靶向的CD19。我们的模块化设计仅靶向癌细胞，与抗CD19 CAR-T细胞联合使用时，它可减少至少两种癌细胞系中的增殖和转移。
