Immune checkpoint inhibitors: From friend to foe

Abstract

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.

Keywords: Auto-immunity; Immune checkpoint inhibitors; Immune-related adverse effects; Inflammation; Rheumatoid arthritis.

Graphical abstract

Fig. 1

Immune response regulation by ICIs. Cancer cells express ligands for the PD-1 expressed on the T cells. PD-L1 of cancer cells interacts with the PD-1 on T cells to block the subsequent signalling required to activate anti-tumour response. However, ICIs exhibit competitive binding for PD-1, and they prevent the PD-L1 on cancer cells from interacting with the PD-1. This results in the activation of an anti-tumour immune response mediated by various subsets of T cells.

Fig. 2

Activation of effector T cells. Interaction between the CD28 of T cells and CD80/CD86 of APC is essential for activation of effector T cells. CTLA-4 has higher affinity for CD80/CD86 and therefore inhibits the differentiation of T cells by decreasing IL2 expression and promoting the expression of IL-2Rα (CD25) on activated T cells. Effector T cells are differentiated using clonal proliferation.

Fig. 3

Regulation of Treg and effector T cell activity by ICIs. Tregs orchestrate the suppression of anti-tumour immunity by expressing the CTLA-4 on their surface. CTLA-4 of Tregs interacts with the CD80/CD86 to disrupt the activities of APCs. This in turn impairs the antigen presentation by the APCs enabling the tumour cells to escape anti-tumour immunity. Tregs through PKC signalling is associated with the depletion of CD80/CD86. Moreover, Tregs also expand their population through CD28 costimulatory signals to deplete CD80 and CD86 expression. Therefore, ICIs aid in depletion of Tregs and preservation of effector T cell activities to augment anti-tumour immunity.

Fig. 4

Sub-cellular events leading to various immune responses. TCR interacts with the MHC on the APCs, activating the PLCγ/Ras/Erl-mediated signalling cascade. Similarly, interactions between CD28 and CD80/86 lead to the activation of the PI3K/Akt pathway. These signalling cascades activate transcription factors (AP-1, NFAT, NF-κβ) that promote growth, proliferation, and effector T cell functions. However, interaction of PD-1 with PD-L1 activates BATF that downregulates T cell proliferation and functions.

Fig. 5

ICI-mediated immune-related adverse effects in cancer patients.

Fig. 6

Production of ICI-mediated autoimmune cells and proinflammatory cytokines. The binding between ICI mAb and PD-1 prevents the binding of PD-L1 expressed on cancer cells to the PD-1. It triggers the activation of T cells, followed by their differentiation and secretion of proinflammatory cytokines (IL-2). These outcomes are responsible for inflammatory tissue damage. However, Treg cells have immunosuppressive action. They release IL-10 and TGFβ, leading to the cytolysis of effector T cells.