分泌型MA1CD47-CART细胞对肺腺癌的杀伤作用及机制研究

肿瘤特异性抗原缺乏及肿瘤微环境的免疫抑制作用是当前实体肿瘤CAR-T细胞治疗面临的两大困境。申请人近期研究发现，以MAGE-A1为靶点构建的MAGE-A1-CAR-T细胞能够有效杀伤肺腺癌（J Hematol Oncol 2019）。现有研究及课题组近期的预实验结果显示，全人源CD47-IgG可抑制“促癌”M2-巨噬细胞极化，提高巨噬细胞对肿瘤细胞的吞噬作用；肿瘤微环境中存在SPP1-CCL2-CCR2的交互作用及HIF1α信号通路的激活。鉴于此，本项目拟以MAGE-A1和CD47为靶点，构建分泌型MAGE-A1/CD47-CAR-T细胞，通过抑制肺腺癌免疫微环境中肿瘤细胞-M2型巨噬细胞-内皮细胞间的SPP1-CCL2-CCR2交互作用及细胞内的HIF1α信号通路，减轻肿瘤微环境中的免疫抑制，增强CAR-T细胞对肺腺癌的杀伤作用。本项目的实施将为肺腺癌的免疫治疗提供新的研究思路。

Two critical obstacles of CAR-T cell treatment in solid tumor are as followed: lack of tumor specific antigen and existence of immunosuppression in tumor microenvironment. Based on the previous researches, we confirmed that tumor specific antigen (TSA) MAGE-A1 is an ideal candidate for lung adenocarcinoma (LUAD) therapy and we successfully constructed MAGE-A1-CAR-T cell on the basis of MAGE-A1-scFv, which demonstrated significant tumor-inhibitory role for LUAD. CD47 plays a key function in affecting tumor microenvironment and checkpoint inhibitor targeting CD47 shows magnificent potential for cancer immunotherapy. A fully human CD47-IgG antibody can substantially block CD47-SIRPa signaling pathway, reduce M2-TAM polarization and boosting phagorytosis of macrophage. There exist the crosstalk among SPP1-CCL2-CCR1 and upregulation of HIF1α signaling pathway in tumor microenvironment. On account of the above preliminary data, we thereby assume that a novel secretory type MAGE-A1/CD47-CAR-T cell (MA1CD47-CART) could be constructed by targeting MAGE-A1 and CD47. This MA1CD47-CART could presumably enhance the tumor-killing effectiveness by inhibiting the crosstalk of among SPP1-CCL2-CCR1 and suspending HIF1α signaling pathway, and finally weaken the immunosuppression in tumor microenvironment. Our study is of original innovation and can provide new scheme for immunotherapy of LUAD.