Cancer Immunology and Immunotherapy Group, Trinity Translational Medicine Institute, St. James's Hospital, Dublin, Ireland.
Methods Mol Biol. 2020;2184:233-263. doi: 10.1007/978-1-0716-0802-9_17.
The last century of research in tumor immunology has culminated in the advent of immunotherapy, most notably immune checkpoint inhibitors. These drugs have shown encouraging results across a multitude of malignancies and have shifted the paradigm of cancer treatment. However, no more than 40% of patients treated with these immune checkpoint blockade inhibitors respond. Thus, resistance is a barrier to therapy that remains poorly understood. All cells require energy and biosynthetic precursors for survival, growth, and functioning, where multiple metabolic pathways allow for flexibility in how nutrients are utilized. A defining hallmark of many cancers is altered cellular metabolism, creating an imbalanced demand for nutrients within the tumor microenvironment. Immunometabolism is increasingly understood to be vital to the functions and phenotypes of a myriad of immune cell subsets. In tumors, the high demand for nutrients by the tumor drives competition between tumor cells and infiltrating immune cells, culminating in dysfunctional immune responses. This chapter discusses the recent successes in cancer immunotherapy and highlights challenges to therapy. We also outline the major metabolic processes involved in the generation of an immune response, how this can become dysregulated in the context of the tumor microenvironment, and how this contributes to resistance to immunotherapy. Finally, we explore the potential for targeting immunometabolic pathways to improve immunotherapy, and examine current trials targeting various aspects of metabolism in an attempt to improve the outcomes from immunotherapy.
肿瘤免疫学的上个世纪的研究最终催生了免疫疗法，尤其是免疫检查点抑制剂。这些药物在多种恶性肿瘤中显示出令人鼓舞的效果，改变了癌症治疗的模式。然而，只有不超过 40%的接受这些免疫检查点抑制剂治疗的患者有反应。因此，耐药性是治疗的一个障碍，目前仍了解甚少。所有细胞都需要能量和生物合成前体来生存、生长和发挥功能，其中多种代谢途径允许对营养物质的利用具有灵活性。许多癌症的一个明确特征是细胞代谢发生改变，导致肿瘤微环境中的营养物质需求失衡。免疫代谢越来越被认为对多种免疫细胞亚群的功能和表型至关重要。在肿瘤中，肿瘤对营养物质的高需求促使肿瘤细胞和浸润的免疫细胞之间产生竞争，最终导致免疫功能失调。本章讨论了癌症免疫疗法的最新成功，并强调了治疗的挑战。我们还概述了参与免疫反应产生的主要代谢过程，以及在肿瘤微环境中这些过程如何失调，以及这如何导致对免疫疗法的耐药性。最后，我们探讨了靶向免疫代谢途径以改善免疫疗法的潜力，并研究了目前针对代谢各个方面的临床试验，试图改善免疫疗法的结果。
