乙酰肝素酶会增加CAR-T细胞对肿瘤的侵润以及增加抗肿瘤活性

Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T-lymphocytes

Abstract

Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking effects in solid tumors than in lymphoid malignancies. Although active tumor-mediated immunosuppression may play a role in limiting efficacy, functional changes in T lymphocytes following their ex vivo manipulation may also account for cultured CAR-T cells’ reduced ability to penetrate stroma-rich solid tumors. We therefore studied the capacity of human in vitro-cultured CAR-T cells to degrade components of the extracellular matrix (ECM). In contrast to freshly isolated T lymphocytes, we found that in vitro-cultured T lymphocytes lack expression of the enzyme heparanase (HPSE) that degrades heparan sulphate proteoglycans, which are main components of ECM. We found that HPSE mRNA is down regulated in in vitro-expanded T cells, which may be a consequence of p53 binding to the HPSE gene promoter. We therefore engineered CAR-T cells to express HPSE and showed improved capacity to degrade ECM, which promoted tumor T-cell infiltration and antitumor activity. Employing this strategy may enhance the activity of CAR-T cells in individuals with stroma-rich solid tumors.

乙酰肝素酶会增加CAR-T细胞对肿瘤的侵润以及增加抗肿瘤活性

摘要:
嵌合抗原受体修饰的T细胞过继疗法对实体肿瘤的作用比淋巴组织恶性肿瘤的作用要弱。虽然活性肿瘤细胞介导的免疫抑制可能会限制它的功能，但是T淋巴细胞在体外操作后的功能变化也许是导致CAR-T细胞对基质丰富的实体肿瘤渗透能力减弱的原因。因此，我们研究了人体外培养的CAR-T细胞对细胞外基质（ECM）成份的降解能力。对比于新鲜分离的T淋巴细胞，我们发现体外培养的T淋巴细胞缺乏表达一种酶——乙酰肝素酶（HPSE），它能降解ECM的主要成分硫酸乙酰肝素蛋白多糖。我们发现，体外培养扩增的T细胞的HPSE mRNA下调，这可能是p53结合HPSE基因启动子导致的后果。因此我们设计的CAR-T细胞表达HPSE，提高了降解细胞外基质能力，从而促进对肿瘤细胞的浸润和抗肿瘤活性。使用这种方式会增强CAR-T细胞在对个体间质丰富的实体瘤细胞的活性。
出自爱康得