Tu Violet Y, Ayari Asma, O'Connor Roddy S
Center for Cellular Immunotherapies, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Biological Physics, University of Pennsylvania, Philadelphia, PA 19104, USA.
Antibodies (Basel). 2021 Jun 28;10(3):25. doi: 10.3390/antib10030025.
T cell therapies, including CAR T cells, have proven more effective in hematologic malignancies than solid tumors, where the local metabolic environment is distinctly immunosuppressive. In particular, the acidic and hypoxic features of the tumor microenvironment (TME) present a unique challenge for T cells. Local metabolism is an important consideration for activated T cells as they undergo bursts of migration, proliferation and differentiation in hostile soil. Tumor cells and activated T cells both produce lactic acid at high rates. The role of lactic acid in T cell biology is complex, as lactate is an often-neglected carbon source that can fuel TCA anaplerosis. Circulating lactate is also an important means to regulate redox balance. In hypoxic tumors, lactate is immune-suppressive. Here, we discuss how intrinsic- (T cells) as well as extrinsic (tumor cells and micro-environmental)-derived metabolic factors, including lactate, suppress the ability of antigen-specific T cells to eradicate tumors. Finally, we introduce recent discoveries that target the TME in order to potentiate T cell-based therapies against cancer.
包括嵌合抗原受体（CAR）T细胞疗法在内的T细胞疗法，在血液系统恶性肿瘤中已被证明比实体瘤更有效，因为实体瘤的局部代谢环境具有明显的免疫抑制作用。特别是，肿瘤微环境（TME）的酸性和缺氧特征对T细胞构成了独特的挑战。局部代谢是活化T细胞的一个重要考量因素，因为它们在恶劣环境中会经历迁移、增殖和分化的爆发。肿瘤细胞和活化T细胞都会大量产生乳酸。乳酸在T细胞生物学中的作用很复杂，因为乳酸是一种常被忽视的碳源，可以为三羧酸循环（TCA）的回补反应提供能量。循环中的乳酸也是调节氧化还原平衡的重要手段。在缺氧肿瘤中，乳酸具有免疫抑制作用。在这里，我们讨论内源性（T细胞）以及外源性（肿瘤细胞和微环境）衍生的代谢因子，包括乳酸，如何抑制抗原特异性T细胞根除肿瘤的能力。最后，我们介绍了针对肿瘤微环境的最新发现，以便增强基于T细胞的癌症治疗方法。
