锰介导的增强KLRG1+巨噬细胞功能以增强抗肿瘤免疫反应
Manganese-mediated potentiation of antitumor immune responses by enhancing KLRG1+ Macrophage function
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影响因子:4.7
分区:医学2区 / 药学2区 免疫学3区
发表日期:2024 Nov 15
作者:
Liyan Ge, Hui Guo, Wei Zhou, Weifeng Shi, Jiawei Yue, Yumin Wu
DOI:
10.1016/j.intimp.2024.112951
摘要
锰（Mn）在体内多种生物过程中发挥着关键作用。研究主要集中在其增强免疫细胞功能和激活抗肿瘤免疫反应的能力，特别是在树突状细胞（DCs）、巨噬细胞和T细胞中。肿瘤相关巨噬细胞（TAMs）通常是肿瘤微环境（TME）中最丰富的免疫细胞群体。因此，研究Mn2+调控TAMs参与抗肿瘤免疫的机制具有重要意义，这对于深化我们对癌症生物学的理解和开发新型癌症治疗方法至关重要。在本研究中，我们发现Mn2+处理显著增加了肿瘤组织中的KLRG1+巨噬细胞（KLRG1+ Mφ），且大多数这些细胞表现出M1表型。敲低巨噬细胞中的KLRG1不仅削弱了其诱导下游适应性免疫细胞抗肿瘤免疫的能力，还削弱了它们对肿瘤细胞的直接细胞毒性作用。此外，KLRG1+巨噬细胞极化表型的变化进一步促进了T细胞增殖和CD4+ T细胞向Th1表型的极化，为抗肿瘤免疫反应奠定了基础。本研究扩展了对Mn2+抗肿瘤机制的理解，并首次证明Mn2+可以调节KLRG1+ Mφ的功能，参与抗肿瘤活动。这些发现提示KLRG1可能成为开发新型肿瘤治疗的有前景的靶点。
Abstract
Manganese (Mn) play a crucial role in various biological processes in the body. Studies have primarily focused on their ability to enhance immune cell function and activation against tumors, particularly in dendritic cells (DCs), macrophages, and T cells. Tumor-associated macrophages (TAMs) are often the most abundant immune cell population present in the tumor microenvironment (TME). Thus, it would be valuable to investigate the mechanism by which Mn2+ regulates TAMs' involvement in anti-tumor immunity, as it be crucial for advancing our understanding of cancer biology and developing new treatments for cancer. Here, in the present study we discovered that Mn2+ treatment led to a significant increase in KLRG1+ macrophages (KLRG1+ Mφ) in tumor tissues, and most of these cells exhibited an M1 phenotype. Knocking down KLRG1 in macrophages not only impaired their ability to induce downstream anti-tumor immunity of adaptive immune cells, but also impaired their direct cytotoxicity against tumor cells. Moreover, the changes in the polarization phenotype of KLRG1+ macrophages further lead to T cell proliferation and the polarization of CD4+ T cells towards a Th1 phenotype, thereby establishing a foundation for the antitumor immune response. Our study expands the understanding of the anti-tumor mechanism of Mn2+ and demonstrates, for the first time, that Mn2+ can regulate the function of KLRG1+ Mφ to participate in anti-tumor activities. These findings suggest that KLRG1 may represent a promising target for developing new tumor therapy.