肿瘤细胞治疗研究
英文原题：Disruption of adenosine 2A receptor improves the anti-tumor function of anti-mesothelin CAR T cells both in vitro and in vivo.
嵌合抗原受体（CAR）T 细胞已成功用于治疗血液系统恶性肿瘤，包括急性与慢性淋巴细胞白血病。
嵌合抗原受体（CAR）T细胞已成功用于治疗急性和慢性淋巴细胞白血病等血液系统恶性肿瘤，但迄今其在实体瘤中的研究结果不够理想，部分原因是免疫抑制性肿瘤微环境（TME）。腺苷大量产生是肿瘤诱导TME免疫抑制的重要因素；腺苷通过结合并激活T细胞上的腺苷A2A受体（A2aR），抑制其抗肿瘤应答。既往研究显示，癌细胞产生的腺苷可通过结合并激活T细胞A2aR显著削弱其抗肿瘤活性。在此前工作的基础上，本研究评估使用shRNA破坏A2aR能否增强抗间皮素（MSLN）CAR T细胞在体外和体内的抗肿瘤功能。研究以MSLN阳性人卵巢浆液性癌细胞SKOV3和人结肠癌细胞HCT116为靶细胞，以MSLN阴性人卵巢癌细胞ES2为非靶细胞。结果显示，通过shRNA过表达靶向细胞内源性A2aR，可显著降低CAR T细胞中的A2aR，并显著增强其细胞因子产生及对MSLN阳性癌细胞的体外细胞毒性。更重要的是，在SKOV3异种移植小鼠模型中，抗MSLN CAR-T细胞较未转导T细胞显著降低肿瘤负荷；破坏A2aR的抗MSLN CAR-T细胞抗肿瘤活性又强于野生型抗MSLN CAR-T细胞。综上，shRNA介导的A2aR破坏可增强抗MSLN CAR T细胞体内外抗肿瘤疗效，证明shRNA介导的基因表达修饰可能是改善免疫抑制性TME中CAR T细胞功能的有效策略，并有望改善临床试验治疗结局。
Chimeric antigen receptor (CAR) T cells have been successfully used for the treatment of hematological malignancies including acute and chronic lymphoblastic leukemia. However, results of CAR T cell projects in solid tumors have been less impressive to date, partly because of immunosuppressive tumor microenvironment (TME). It is widely known that high adenosine production is an important factor causing tumor-induced immunosuppression in TME, and adenosine mediates the suppression of anti-tumor T cell responses via binding and signaling through adenosine 2a receptor (A2aR). Previous studies have shown that adenosine generated by cancer cells significantly inhibits T cell anti-tumor activity through binding and then activating adenosine 2A receptors (A2aRs) of T cells. Based on the previous work, in our study, we evaluated whether A2aR disruption by shRNA could enhance the anti-tumor function of anti-mesothelin (MSLN) CAR T cells both in vitro and in vivo. For this goal above, we used MSLN-positive human ovarian serous carcinoma cells (SKOV3) and human colon cancer cells (HCT116) as target cancer cells while MSLN-negative human ovarian cancer cells (ES2) as non-target cancer cells. We observed that targeting cell-intrinsic A2aR through shRNA overexpression caused significant A2aR disruption in CAR T cells and profoundly increased CAR T cell efficacy in both CAR T cell cytokine production and cytotoxicity towards MSLN-positive cancer cells in vitro. More importantly, in SKOV3 xenograft mouse models, anti-MSLN CAR-T cells significantly reduced the tumor burden compared with non-transduced T cells, and the anti-tumor activity of A2aR-disrupted anti-MSLN CAR-T cells was stronger than that of wild-type anti-MSLN CAR-T cells. Altogether, our study showed enhanced anti-tumor efficacy caused by shRNA-mediated A2aR disruption in anti-MSLN CAR T cells both in vitro and in vivo, which proved that shRNA-mediated modification of gene expression might be an excellent strategy for improving CAR T cell function in immunosuppressive tumor microenvironment (TME) and could potentially improve the outcome of treatment in clinical trials.
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