Caruana Ignazio, Savoldo Barbara, Hoyos Valentina, Weber Gerrit, Liu Hao, Kim Eugene S, Ittmann Michael M, Marchetti Dario, Dotti Gianpietro
Center for Cell and Gene Therapy, Baylor College of Medicine and Houston Methodist Hospital, Houston, Texas, USA.
1] Center for Cell and Gene Therapy, Baylor College of Medicine and Houston Methodist Hospital, Houston, Texas, USA. [2] Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
Nat Med. 2015 May;21(5):524-9. doi: 10.1038/nm.3833. Epub 2015 Apr 13.
Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking therapeutic effects in solid tumors than in lymphoid malignancies. Although active tumor-mediated immunosuppression may have a role in limiting the efficacy of CAR-T cells, functional changes in T lymphocytes after their ex vivo manipulation may also account for the reduced ability of cultured CAR-T cells to penetrate stroma-rich solid tumors compared with lymphoid tissues. 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), which degrades heparan sulfate proteoglycans, the main components of ECM. We found that HPSE mRNA is downregulated in in vitro-expanded T cells, which may be a consequence of p53 (officially known as TP53, encoding tumor protein 53) binding to the HPSE gene promoter. We therefore engineered CAR-T cells to express HPSE and showed their improved capacity to degrade the ECM, which promoted tumor T cell infiltration and antitumor activity. The use of this strategy may enhance the activity of CAR-T cells in individuals with stroma-rich solid tumors.
嵌合抗原受体（CAR）重定向T淋巴细胞（CAR-T细胞）的过继性转移在实体瘤中的治疗效果不如在淋巴恶性肿瘤中显著。尽管活跃的肿瘤介导的免疫抑制可能在限制CAR-T细胞的疗效方面发挥作用，但T淋巴细胞在体外操作后的功能变化也可能是导致培养的CAR-T细胞与淋巴组织相比穿透富含基质的实体瘤能力降低的原因。因此，我们研究了人体外培养的CAR-T细胞降解细胞外基质（ECM）成分的能力。与新鲜分离的T淋巴细胞不同，我们发现体外培养的T淋巴细胞缺乏降解硫酸乙酰肝素蛋白聚糖（ECM的主要成分）的酶乙酰肝素酶（HPSE）的表达。我们发现HPSE mRNA在体外扩增的T细胞中下调，这可能是p53（正式名称为TP53，编码肿瘤蛋白53）与HPSE基因启动子结合的结果。因此，我们对CAR-T细胞进行基因改造使其表达HPSE，并显示它们降解ECM的能力得到改善，这促进了肿瘤T细胞浸润和抗肿瘤活性。使用这种策略可能会增强CAR-T细胞在富含基质的实体瘤患者中的活性。
