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Review
. 2024 May 17;25(10):5490.
doi: 10.3390/ijms25105490.

Immunomodulatory Precision: A Narrative Review Exploring the Critical Role of Immune Checkpoint Inhibitors in Cancer Treatment

Junyu Qiu  1   2 , Zilin Cheng  1   2 , Zheng Jiang  1   2 , Luhan Gan  1   3 , Zixuan Zhang  1   2 , Zhenzhen Xie  1
Affiliations
Review

Immunomodulatory Precision: A Narrative Review Exploring the Critical Role of Immune Checkpoint Inhibitors in Cancer Treatment

Junyu Qiu et al. Int J Mol Sci. .

Abstract

An immune checkpoint is a signaling pathway that regulates the recognition of antigens by T-cell receptors (TCRs) during an immune response. These checkpoints play a pivotal role in suppressing excessive immune responses and maintaining immune homeostasis against viral or microbial infections. There are several FDA-approved immune checkpoint inhibitors (ICIs), including ipilimumab, pembrolizumab, and avelumab. These ICIs target cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L1). Furthermore, ongoing efforts are focused on developing new ICIs with emerging potential. In comparison to conventional treatments, ICIs offer the advantages of reduced side effects and durable responses. There is growing interest in the potential of combining different ICIs with chemotherapy, radiation therapy, or targeted therapies. This article comprehensively reviews the classification, mechanism of action, application, and combination strategies of ICIs in various cancers and discusses their current limitations. Our objective is to contribute to the future development of more effective anticancer drugs targeting immune checkpoints.

Keywords: anti-cancer drugs; cancer treatment; combination immunotherapies; immune checkpoint inhibitors (ICIs); immune response.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Mechanisms of action of PD-1/PD-L1, CTLA-4, and CD80/CD86, and the regulating role of CISH in T cells’ activities. CD80/86 expressed on APCs or tumor cells interacts with CTLA-4 and its homologous CD28, or PD-L1 interacts with its receptor PD1 on the surface of the activated T cells, respectively. Such interactions result in the activation of SHP2 and PP2A and the downregulation of the PI3K/AKT axis. CISH could regulate T cell activities via the lysis of PLC-γ by the proteasome, but not via PI3K/AKT axis. CISH knockout could enhance tumor-infiltrating T cell activity, especially when combined with PD1 inhibitors. ICIs targeting different molecules are also listed. Abbreviations: TCR: T-cell receptor; PD1: programmed cell death protein-1; PD-L1: programmed cell death protein ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; MHC: major histocompatibility complex; SHP-2: Src homology region 2-containing protein tyrosine phosphatase 2: AKT: protein kinase B; PI3K: phosphatidylinositol 3-phosphokinase; PP2A: protein phosphatase 2A; PLC-γ: phospholipase C; CISH: cytokine-inducible SH2-containing protein.
Figure 2
Figure 2
Molecular mechanisms of ICIs in various cancers. The application of ICIs in these five cancers has reached a very advanced level. In terms of molecular mechanisms, ICIs are mainly mediated by PD-1 and CTLA-4, but the effectiveness of the same drug varies in different cancers. Abbreviations: NSCLC: non-small cell lung cancer; UC: urothelial carcinoma; RCC: renal cell carcinoma.
Figure 3
Figure 3
Immunosuppressive dynamics in the tumor microenvironment (TME): MDSC-mediated modulation of immune responses. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immune cells that play a significant role in the tumor microenvironment. In cancer, MDSCs are induced and accumulate in response to factors released by tumor cells. Excessive production of NO by iNOS in MDSCs can suppress T-cell function and promote immune evasion. NO inhibits T-cell receptor signaling by nitrosylating critical signaling proteins, reducing IL-2 production, and impairing cytotoxic activity. This dampens T cell effector functions and promotes an immunosuppressive environment. Furthermore, PNT, which is formed by the reaction between NO and superoxide radicals, has been implicated in inducing apoptosis or dysfunction of activated T cells. MDSCs secrete immunosuppressive cytokines such as IL-10 and TGF-ß. These cytokines can modulate cysteine metabolism within the tumor microenvironment, promoting an immunosuppressive state that inhibits T-cell responses. CD39 is an ectonucleotidase that hydrolyzes ATP into AMP and subsequently into ADP; CD73 converts AMP into adenosine. This further promotes the accumulation of adenosine in the tumor microenvironment or sites of inflammation. Adenosine binds to specific G-protein-coupled receptors on the surface of T cells, particularly the AZA and A2B adenosine receptors. Activation of these receptors inhibits T-cell receptor signaling pathways and downstream activation events, thereby suppressing T-cell activation, proliferation, and cytokine production. ARG-1 competes with T cells for the essential amino acid L-arginine, leading to its depletion in the tumor microenvironment or inflammatory sites. L-arginine is necessary for T-cell activation, proliferation, and effector functions. Therefore, decreased availability of L-arginine can impair T-cell responses. PD-1 is an immune checkpoint receptor expressed on the surface of activated T cells. When PD-1 binds to its ligands, such as PD-L1 or PD-L2, which are expressed by MDSCs and other immune cells, it delivers inhibitory signals that attenuate T-cell activation and effector functions. TGF-ß signaling can directly inhibit the activation and cytotoxicity of NK cells. It dampens NK cell receptor-mediated signaling pathways, such as those initiated by activating receptors like NKG2D or DNAM-1, which are essential for NK cell recognition and the killing of target cells. Both IL-10 and TGF-ß can promote the differentiation and expansion of regulatory T cells. They contribute to the generation of a population of immunosuppressive Tregs that can suppress excessive immune responses. Abbreviations: MDSCs: myeloid-derived suppressor cells; NO: nitric oxide; iNOS: inducible nitric oxide synthase; PNT: peroxynitrite.
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