Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland.
J Immunother Cancer. 2020 Dec;8(2). doi: 10.1136/jitc-2020-001408.
Tumor-associated macrophage (TAM) phagocytic activity is emerging as a new mechanism to harness for cancer treatment. Currently, many approaches are investigated at the preclinical level and some modalities have now reached clinical trials, including the targeting of the phagocytosis inhibitor CD47. The rationale for increasing TAM phagocytic activity is to improve innate anticancer immunity, and to promote T-cell mediated adaptive immune responses. In this context, a clear understanding of the impact of TAM phagocytosis on both innate and adaptive immunity is critical. Indeed, uncertainties persist regarding the capacity of TAM to present tumor antigens to CD8 T cells by cross-presentation. This process is critical for an optimal cytotoxic T-cell immune response and can be mediated by dendritic cells but also potentially by macrophages. In addition, the engulfment of cancer cells affects TAM functionality, as apoptotic cell uptake (a process termed efferocytosis) promotes macrophage anti-inflammatory functions. Because of the abundance of TAM in most solid tumors and the common use of apoptosis inducers such as radiotherapy to treat patients with cancer, efferocytosis potentially affects the overall immune balance within the tumor microenvironment (TME). In this review, we will discuss how cancer cell phagocytosis by TAM impacts antitumor immunity. First, we will focus on the potential of the phagocytic activity of TAM per se to control tumor progression. Second, we will examine the potential of TAM to act as antigen presenting cells for tumor specific CD8 T cells, considering the different characteristics of this process in the tumor tissue and at the molecular level. Finally, we will see how phagocytosis and efferocytosis affect TAM functionality and how these mechanisms impact on antitumor immunity. A better understanding of these aspects will enable us to better predict and interpret the consequences of cancer therapies on the immune status of the TME. Future cancer treatment regimens can thereby be designed to not only impact directly on cancer cells, but also to favorably modulate TAM phagocytic activity to benefit from the potential of this central immune player to achieve more potent therapeutic efficacy.
肿瘤相关巨噬细胞（TAM）的吞噬活性正成为一种新的治疗癌症的机制。目前，许多方法正在进行临床前研究，一些方法已经进入临床试验，包括靶向吞噬抑制剂 CD47。增加 TAM 吞噬活性的基本原理是改善先天抗肿瘤免疫，并促进 T 细胞介导的适应性免疫反应。在这种情况下，清楚地了解 TAM 吞噬作用对先天和适应性免疫的影响至关重要。事实上，关于 TAM 通过交叉呈递将肿瘤抗原呈递给 CD8 T 细胞的能力仍然存在不确定性。这个过程对于最佳的细胞毒性 T 细胞免疫反应至关重要，并且可以由树突状细胞介导，但也可能由巨噬细胞介导。此外，癌细胞的吞噬作用会影响 TAM 的功能，因为凋亡细胞的摄取（称为吞噬作用）促进巨噬细胞的抗炎功能。由于 TAM 在大多数实体瘤中丰富，并且经常使用凋亡诱导剂（如放射疗法）来治疗癌症患者，吞噬作用可能会影响肿瘤微环境（TME）中的整体免疫平衡。在这篇综述中，我们将讨论 TAM 吞噬癌细胞如何影响抗肿瘤免疫。首先，我们将重点讨论 TAM 吞噬活性本身控制肿瘤进展的潜力。其次，我们将研究 TAM 作为肿瘤特异性 CD8 T 细胞抗原呈递细胞的潜力，同时考虑到这一过程在肿瘤组织和分子水平上的不同特征。最后，我们将看到吞噬作用和吞噬作用如何影响 TAM 的功能，以及这些机制如何影响抗肿瘤免疫。更好地了解这些方面将使我们能够更好地预测和解释癌症治疗对 TME 免疫状态的影响。未来的癌症治疗方案可以不仅直接影响癌细胞，而且还可以有利地调节 TAM 的吞噬活性，以利用这种中央免疫细胞发挥更大的治疗效果。
