Engineering amino acid uptake or catabolism promotes CAR T-cell adaption to the tumor environment.
Engineering amino acid uptake or catabolism promotes CAR T-cell adaption to the tumor environment.
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DOI：
10.1182/bloodadvances.2022008272
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发表时间：
2023-05-09
期刊：
影响因子：
7.5
通讯作者：
De Santo, Carmela
中科院分区：
文献类型：
--
作者：
Panetti, Silvia;McJannett, Nicola;Fultang, Livingstone;Booth, Sarah;Gneo, Luciana;Scarpa, Ugo;Smith, Charles;Vardon, Ashley;Vettore, Lisa;Whalley, Celina;Pan, Yi;Varnai, Csilla;Endou, Hitoshi;Barlow, Jonathan;Tennant, Daniel;Beggs, Andrew;Mussai, Francis;De Santo, Carmela
将CAR T细胞工程化以表达SLC 7A 5/SLC 7A 11或下游腺苷酸酶增强了癌症环境中的CAR T细胞活性。癌细胞从细胞外空间摄取氨基酸以驱动细胞增殖和活力。免疫细胞应用类似的机制，导致常规T细胞或嵌合抗原受体（CAR）T细胞与肿瘤细胞之间竞争环境中氨基酸的有限可用性。我们证明T细胞可以被重新工程化以表达SLC 7A 5或SLC 7A 11跨膜氨基酸转运蛋白以及汽车。转运蛋白修饰在低色氨酸或胱氨酸条件下增加CAR T细胞增殖，而不损失CAR细胞毒性或增加耗竭。转录组学和表型分析揭示，下游SLC 7A 5/SLC 7A 11修饰的CAR T细胞上调细胞内腺苷酸酶表达和活性。反过来，我们设计并表型了另一代CAR T细胞，这些细胞表达功能性β-内酰胺酶1/β-内酰胺酶2酶，并具有增强的CAR T细胞增殖和抗肿瘤活性。因此，CAR T细胞可以适应癌症的氨基酸代谢微环境，这是迄今为止公认但尚未解决的成功CAR T细胞治疗的障碍。
Engineering CAR T cells to express SLC7A5/SLC7A11 or downstream arginase enzymes enhances CAR T-cell activity in the cancer environment. Cancer cells take up amino acids from the extracellular space to drive cell proliferation and viability. Similar mechanisms are applied by immune cells, resulting in the competition between conventional T cells, or indeed chimeric antigen receptor (CAR) T cells and tumor cells, for the limited availability of amino acids within the environment. We demonstrate that T cells can be re-engineered to express SLC7A5 or SLC7A11 transmembrane amino acid transporters alongside CARs. Transporter modifications increase CAR T-cell proliferation under low tryptophan or cystine conditions with no loss of CAR cytotoxicity or increased exhaustion. Transcriptomic and phenotypic analysis reveals that downstream, SLC7A5/SLC7A11–modified CAR T cells upregulate intracellular arginase expression and activity. In turn, we engineer and phenotype a further generation of CAR T cells that express functional arginase 1/arginase 2 enzymes and have enhanced CAR T-cell proliferation and antitumor activity. Thus, CAR T cells can be adapted to the amino acid metabolic microenvironment of cancer, a hitherto recognized but unaddressed barrier for successful CAR T-cell therapy.
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影响因子：
17.1
作者：
Jan M;Scarfò I;Larson RC;Walker A;Schmidts A;Guirguis AA;Gasser JA;Słabicki M;Bouffard AA;Castano AP;Kann MC;Cabral ML;Tepper A;Grinshpun DE;Sperling AS;Kyung T;Sievers QL;Birnbaum ME;Maus MV;Ebert BL
通讯作者：
Ebert BL
影响因子：
50.3
作者：
Timmerman LA;Holton T;Yuneva M;Louie RJ;Padró M;Daemen A;Hu M;Chan DA;Ethier SP;van 't Veer LJ;Polyak K;McCormick F;Gray JW
通讯作者：
Gray JW
影响因子：
20.3
作者：
Le Dieu, Rifca;Taussig, David C.;Gribben, John G.
通讯作者：
Gribben, John G.
影响因子：
45.3
作者：
Shah, Nirali N.;Lee, Daniel W.;Mackall, Crystal L.
通讯作者：
Mackall, Crystal L.
影响因子：
12.4
作者：
Ritchie, David S.;Neeson, Paul J.;Prince, H. Miles
通讯作者：
Prince, H. Miles