Rajak Prem
Toxicology Research Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol, West Bengal, India.
Toxicol Rep. 2025 Apr 24;14:102033. doi: 10.1016/j.toxrep.2025.102033. eCollection 2025 Jun.
Immune checkpoints are crucial in regulating the activation of cell-mediated and humoral immune responses. However, cancer cells hijack this mechanism to evade the immune surveillance and anti-cancer response. Typically, receptors like PD-1 and CTLA4, expressed on immune cells, prevent the activation and differentiation of T cells. They also inhibit the development of autoimmune reactions. However, ligands such as PD-L1 for the receptor PD-1 are also expressed on the surface of cancer cells that help prevent the activation of anti-cancer immune responses by blocking the signalling pathways mediated by PD-1 and CTLA4. Immune checkpoint inhibitors (ICIs) have promising therapeutic efficacy for treating several cancers by activating T cells and their differentiation into effector cells against tumours. Nonetheless, hyperactivated immune cells usually contribute to detrimental issues, also known as immune-related adverse effects (IrAE). IrAEs have been observed in multiple organs, leading to neurological issues, colitis, endocrine dysfunction, renal issues, hepatitis, pneumonitis, and dermatitis. The interplay between hyperactivated T cells and Treg cells helps in orchestrating the development of autoimmunity. Moreover, the crosstalk between proinflammatory interleukins and the development of autoantibodies also mediates the multiorgan effects of ICIs in cancer patients. IrAEs are generally managed by terminating the ICI therapy, reducing the ICI dose, and by using corticosteroids to subvert inflammation. Therefore, the present review aims to delineate the impacts of ICIs on the development of autoimmune diseases and inflammatory outcomes in cancer patients. In addition, mechanistic insight involving immune cells, cytokines, and autoantibodies for ICI-mediated IrAEs will also be discussed with updated findings in this field.
免疫检查点在调节细胞介导的免疫反应和体液免疫反应的激活中起着关键作用。然而，癌细胞会利用这一机制来逃避免疫监视和抗癌反应。通常，免疫细胞上表达的PD-1和CTLA4等受体可阻止T细胞的激活和分化。它们还能抑制自身免疫反应的发展。然而，受体PD-1的配体如PD-L1也在癌细胞表面表达，通过阻断由PD-1和CTLA4介导的信号通路，有助于防止抗癌免疫反应的激活。免疫检查点抑制剂（ICI）通过激活T细胞并使其分化为针对肿瘤的效应细胞，在治疗多种癌症方面具有有前景的治疗效果。尽管如此，过度激活的免疫细胞通常会导致有害问题，也称为免疫相关不良反应（IrAE）。在多个器官中都观察到了IrAE，导致神经问题、结肠炎、内分泌功能障碍、肾脏问题、肝炎、肺炎和皮炎。过度激活的T细胞与调节性T细胞之间的相互作用有助于协调自身免疫的发展。此外，促炎白细胞介素与自身抗体的发展之间的相互作用也介导了ICI对癌症患者的多器官影响。IrAE通常通过终止ICI治疗、降低ICI剂量以及使用皮质类固醇来减轻炎症来进行管理。因此，本综述旨在阐述ICI对癌症患者自身免疫性疾病发展和炎症结果的影响。此外，还将结合该领域的最新研究结果，讨论涉及免疫细胞、细胞因子和自身抗体的ICI介导的IrAE的作用机制。
