Oncolytic adenovirus-mediated expression of decorin facilitates CAIX-targeting CAR-T therapy against renal cell carcinoma.
Oncolytic adenovirus-mediated expression of decorin facilitates CAIX-targeting CAR-T therapy against renal cell carcinoma.
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溶瘤腺病毒介导的核心蛋白聚糖表达促进针对肾细胞癌的 CAIX 靶向 CAR-T 疗法
DOI：
10.1016/j.omto.2021.11.018
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发表时间：
2022-03-17
期刊：
影响因子：
--
通讯作者：
Zheng J
中科院分区：
文献类型：
--
作者：
Zhang C;Fang L;Wang X;Yuan S;Li W;Tian W;Chen J;Zhang Q;Zhang Y;Zhang Q;Zheng J
尽管嵌合抗原受体T细胞（CAR-T）疗法已成功用于血液恶性肿瘤，但其对实体瘤的有效性较低。主要原因是免疫微环境限制了CAR-T细胞在肿瘤中的浸润和增殖。溶瘤病毒治疗已成为一种新的免疫原性治疗，以增强抗肿瘤免疫应答。在这里，我们将携带核心蛋白聚糖的溶瘤腺病毒与靶向碳酸酐酶IX（CAIX）的CAR-T组合，以执行对肾癌细胞的抗肿瘤活性。我们发现OAV-Decorin联合CAIX-CAR-T显著降低了肿瘤负荷，通过抑制胶原纤维的分布改变了细胞外基质（ECM）的组成，降低了肿瘤细胞中TGF-β的表达，增强了IFN-γ的分泌，并获得了更高数量的CAR-T细胞。联合治疗模式显示小鼠存活延长。将OAV-核心蛋白聚糖瘤内注射到荷瘤免疫活性小鼠中激活了炎性免疫状态并导致肿瘤消退。这些数据支持进一步研究实体瘤中OAV-核心蛋白聚糖和CAIX-CAR-T细胞的组合。结果表明，溶瘤腺病毒介导的核心蛋白聚糖表达激活了炎症免疫状态。OAV-核心蛋白聚糖与CAIX靶向CAR-T细胞的组合表现出显著降低的肾肿瘤负荷，并改变了细胞外基质的组成。OAV-Decorin有望被开发为CAR-T细胞治疗方法的有效增强剂。
Although chimeric antigen receptor T cell (CAR-T) therapy has been successful for hematological malignancies, it is less effective for solid tumors. The primary reason is that the immune microenvironment restricts CAR-T cells from infiltrating and proliferating in tumors. Oncolytic virotherapy has emerged as a novel immunogenic therapy to augment antitumor immune response. Here we combined an oncolytic adenovirus carrying decorin with a CAR-T targeting carbonic anhydrase IX (CAIX) to perform the antitumor activity for renal cancer cells. We found that OAV-Decorin combined with CAIX-CAR-T exhibited significantly reduced tumor burden, altered the composition of extracellular matrix (ECM) by inhibiting the distribution of collagen fibers, decreased the expression of TGF-β in tumor cells, enhanced IFN-γ secretion, and obtained higher numbers of CAR-T cells. The combination treatment modality showed prolonged mice survival. The intratumoral injection of OAV-Decorin into tumor-bearing immunocompetent mice activated the inflammatory immune status and resulted in tumor regression. These data supported further investigation of the combination of OAV-Decorin and CAIX-CAR-T cells in solid tumors. It was shown that decorin expression mediated by oncolytic adenovirus activated the inflammatory immune status. OAV-Decorin combined with CAIX-targeted CAR-T cells exhibited significantly reduced renal tumor burden and altered the composition of extracellular matrix. OAV-Decorin is potent to be developed as an effective enhancer of CAR-T cells therapeutic approach.
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影响因子：
3.7
作者：
Ahtiainen L;Mirantes C;Jahkola T;Escutenaire S;Diaconu I;Osterlund P;Kanerva A;Cerullo V;Hemminki A
通讯作者：
Hemminki A
影响因子：
4.8
作者：
Iqbal Yatoo M;Hamid Z;Rather I;Nazir QUA;Bhat RA;Ul Haq A;Magray SN;Haq Z;Sah R;Tiwari R;Natesan S;Bilal M;Harapan H;Dhama K
通讯作者：
Dhama K
影响因子：
--
作者：
Oh E;Choi IK;Hong J;Yun CO
通讯作者：
Yun CO
影响因子：
5.9
作者：
Hu X;Villodre ES;Larson R;Rahal OM;Wang X;Gong Y;Song J;Krishnamurthy S;Ueno NT;Tripathy D;Woodward WA;Debeb BG
通讯作者：
Debeb BG
影响因子：
6.4
作者：
Baniak, Nicholas;Flood, Trevor A.;Hirsch, Michelle S.
通讯作者：
Hirsch, Michelle S.