PEN-2蛋白：调控BCMA切割，提高抗BCMA CAR T细胞疗效新靶点？

多发性骨髓瘤（MM）中，抗B细胞成熟抗原（BCMA）嵌合抗原受体（CAR）T细胞治疗后，残余肿瘤细胞BCMA丢失或下调是复发的原因之一。调控BCMA切割，增加膜表面BCMA（mBCMA）表达可以增强CAR T细胞对MM细胞的识别，从而提高疗效。申请者前期发现PEN-2蛋白是调控BCMA切割的关键因子。那么PEN-2蛋白调控BCMA切割的具体机制是什么？能否作为临床提高抗BCMA CAR T细胞疗效的靶点？本项目从细胞系、原代标本和公共数据库验证PEN-2蛋白是调控BCMA切割的关键因素，分析PEN-2蛋白在MM细胞增殖存活中的作用，并深入探索PEN-2蛋白调控BCMA切割的内在机制，评估PEN-2蛋白作为临床治疗靶点的潜力。本课题的完成，有望首次提出PEN-2蛋白是调控BCMA切割的关键因素，为增强BCMA CAR T疗效提供新的的治疗靶点。

In multiple myeloma (MM), the loss or down-regulation of residual MM cells BCMA after anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell treatment, is one determinant of recurrence. Regulating BCMA cleavage and increasing the expression of BCMA (mBCMA) on the membrane can enhance CAR T cell recognition of MM cells, thereby improving the antitumor efficacy. The applicant found that the PEN-2 protein is a key factor regulating BCMA cleavage. So what is the mechanism of PEN-2 regulating BCMA cleavage? Can it be used as a clinical target to improve the efficacy of anti-BCMA CAR T cells? This project verifies that PEN-2 is a key factor in regulating BCMA cleavage from cell lines, primary specimens and public databases. It analyzes the role of PEN-2 protein in the proliferation and survival of MM cells by both in vivo and in vitro experiments. Further more, we explored the internal mechanism of how PEN-2 regulates BCMA cleavage. Also, we evaluate potential of PEN-2 protein as a clinical therapeutic target. The completion of this project is expected to propose for the first time that the PEN-2 protein is a key factor in regulating BCMA cleavage, providing a new therapeutic target for enhancing the efficacy of BCMA CAR T.