Gaggero Silvia, Witt Kristina, Carlsten Mattias, Mitra Suman
Univ. Lille, CNRS, INSERM, CHU Lille, Institut pour la Recherche contre le Cancer de Lille, UMR9020 - UMR-S 1277 - CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France.
Center for Hematology and Regenerative Medicine, Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
Front Immunol. 2021 Jan 29;11:621225. doi: 10.3389/fimmu.2020.621225. eCollection 2020.
Natural killer (NK) cells are endowed with germline-encoded receptors that enable them to detect and kill malignant cells without prior priming. Over the years, overwhelming evidence has identified an essential role for NK cells in tumor immune surveillance. More recently, clinical trials have also highlighted their potential in therapeutic settings. Yet, data show that NK cells can be dysregulated within the tumor microenvironment (TME), rendering them ineffective in eradicating the cancer cells. This has been attributed to immune suppressive factors, including the tumor cells , stromal cells, regulatory T cells, and soluble factors such as reactive oxygen species and cytokines. However, the TME also hosts myeloid cells such as dendritic cells, macrophages, neutrophils, and myeloid-derived suppressor cells that influence NK cell function. Although the NK-myeloid cell crosstalk can promote anti-tumor responses, myeloid cells in the TME often dysregulate NK cells direct cell-to-cell interactions down-regulating key NK cell receptors, depletion of nutrients and growth factors required for NK cell growth, and secretion of metabolites, chemokines and cytokines that ultimately alter NK cell trafficking, survival, and cytotoxicity. Here, we review the complex functions of myeloid-derived cytokines in both supporting and suppressing NK cells in the TME and how NK cell-derived cytokines can influence myeloid subsets. We discuss challenges related to these interactions in unleashing the full potential of endogenous and adoptively infused NK cells. Finally, we present strategies aiming at improving NK cell-based cancer immunotherapies pathways that are involved in the NK-myeloid cell crosstalk in the TME.
自然杀伤（NK）细胞具有种系编码的受体，使它们能够在无需预先致敏的情况下检测并杀死恶性细胞。多年来，大量证据表明NK细胞在肿瘤免疫监视中发挥着重要作用。最近，临床试验也凸显了它们在治疗方面的潜力。然而，数据显示NK细胞在肿瘤微环境（TME）中可能会失调，导致它们在根除癌细胞方面无效。这归因于免疫抑制因子，包括肿瘤细胞、基质细胞、调节性T细胞以及活性氧和细胞因子等可溶性因子。然而，TME中还存在髓系细胞，如树突状细胞、巨噬细胞、中性粒细胞和髓系来源的抑制细胞，它们会影响NK细胞的功能。尽管NK细胞与髓系细胞的相互作用可以促进抗肿瘤反应，但TME中的髓系细胞常常会使NK细胞失调，通过直接的细胞间相互作用下调关键的NK细胞受体，耗尽NK细胞生长所需的营养物质和生长因子，并分泌代谢产物、趋化因子和细胞因子，最终改变NK细胞的迁移、存活和细胞毒性。在此，我们综述了髓系来源的细胞因子在TME中支持和抑制NK细胞的复杂功能，以及NK细胞来源的细胞因子如何影响髓系亚群。我们讨论了在释放内源性和过继输注的NK细胞的全部潜力方面与这些相互作用相关的挑战。最后，我们提出了旨在改善基于NK细胞的癌症免疫疗法的策略——涉及TME中NK细胞与髓系细胞相互作用的途径。
