Cancer cells take up amino acids from the extracellular space to drive cell proliferation and viability. Similar mechanisms are employed by immune cells. The result is competition between conventional T cells, or indeed CAR-T cells, and tumour cells for 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 chimeric antigen receptors (CAR). 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 which express functional Arginase I/Arginase II enzymes, and have enhanced CAR-T cell proliferation and anti-tumour activity. Thus CAR-T cells can be adapted to the amino acid metabolic microenvironment of cancer, a hitherto recognised but unaddressed barrier to successful CAR-T therapy.
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