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. 2024 Feb 23;3(2):100146. doi: 10.1016/j.cellin.2024.100146

PD-1-mediated inhibition of T cell activation: Mechanisms and strategies for cancer combination immunotherapy

Rui Liu a,b,c,d,e, Hui-Fang Li a,b,c,d,e, Shu Li a,b,c,d,e,∗
PMCID: PMC10901852  PMID: 38425643

Abstract

The programmed cell death 1 (PD-1) immune checkpoint of co-inhibitory signaling plays crucial roles in controlling the magnitude and duration of T cell activation to limit tissue damage and maintain self-tolerance. Cancer cells hijack the co-inhibitory pathway and escape immune surveillance by overexpressing the PD-1 ligand PD-L1. Immune checkpoint inhibitors, such as PD-1 blocking antibody have been approved for tumor immunotherapy. However, not all patients can benefit from PD-1 monotherapy. Combination immunotherapy based on PD-1 axis blockade substantially improves clinical anti-tumor efficacy. In this review, we briefly summarize the current progress on the mechanisms of PD-1-mediated inhibition of T cell activation and strategies for cancer combination immunotherapy.

1. Introduction

Cancer represents a substantial global health challenge and ranks among the most pressing health issues worldwide. Conventional therapies, including chemoradiotherapy, are not effective in removing tumors and limited by serious side effects and drug resistance (Rallis et al., 2021; Wang et al., 2017). It is necessary to develop new therapies to surmount the drawbacks. The immune system is crucial in immune surveillance, as immune cells infiltrate into tumor tissues and participate in regulating tumor progression (Boussiotis, 2016; Waldman et al., 2020). An effective immune response can either eliminate malignant cells or inhibit their malignant phenotype (Zhang & Zhang, 2020). However, a variety of mechanisms to evade immune surveillance have been evolved by tumor cells, such as up-regulation of negative regulatory pathways, defective antigen presentation, leading to blocked immune cell effector function and cancellation of anti-tumor immune response (Chen et al., 2018; Schreiber et al., 2011; Vinay et al., 2015).

Immunotherapy is a monumental breakthrough in cancer treatment, which aims to boost natural defenses to eliminate malignant cells (Waldman et al., 2020). In various types of immunotherapy, such as oncolytic viruses, cytokines, adoptive cell transfer and so on, immune checkpoint blockade (ICB) is at the forefront of clinical cancer immunotherapy (Andtbacka et al., 2015; Brahmer et al., 2012; Lin et al., 2022; Rosenberg et al., 1985a; Rosenberg et al., 1985b; Rosenberg & Restifo, 2015; Wang et al., 2022; Yi et al., 2022). James P. Allison and Tasuku Honjo were awarded the Nobel Prize in Physiology or Medicine in 2018 for the discovery of treating cancer by suppressing negative immune regulation (Ishida et al., 1992; Leach et al., 1996). Their research indicates that the immune checkpoints PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) act as brakes in immune system, and immune checkpoint inhibition may significantly reactivate T cells and eliminate cancer cells (Freeman et al., 2000; Hodi et al., 2003; Kwon et al., 1997; Nishimura et al., 1999). Accumulating evidence suggests that targeting blockade of PD-1 axis enhances an effective immune response to against cancer cells and is associated with significant clinical responses in a wide range of cancer patients. (Boussiotis, 2016; Han et al., 2020). In this minireview, we outline the biological function of PD-1 axis, as well as the recent findings on PD-1 signaling antagonizing common cytokine receptor γ chain (γc) family cytokine-triggered immune activation, their associations with immunotherapy and potential clinical applications.

2. Overview of PD-1 signaling

PD-1 was first identified in 1992 as a putative mediator of apoptosis (Ishida et al., 1992). Subsequent evidence suggests that PD-1 is a key co-inhibitory receptor in the B7-CD28-CTLA4 family and plays a role in restraining immune system hyperactivation (Boussiotis, 2016). PD-L1 is the ligand for PD-1, which is expressed by APCs stimulated with pro-inflammatory cytokines, such as interferon-γ (IFN-γ) and can also be constitutively expressed by non-hematopoietic tissues (Dong et al., 1999; Freeman et al., 2000; Strome et al., 2003). The PD-1 axis negatively regulates T cell activation and controls the magnitude and duration of T cell responses to limit tissue damage and maintain self-tolerance under physiological and pathological conditions (Boussiotis, 2016). T cells within peripheral tissues upregulate PD-1 at the mRNA level early after activation. Late after activation in peripheral tissues, PD-1 is further upregulated transcriptionally, leading to greater surface expression of PD-1, which binds to its ligands, thereby promoting T cell exhaustion at sites of infection or when confronted with neoplasms.

PD-1 is a type 1 transmembrane glycoprotein belonging to the immunoglobulin superfamily (Oestreich et al., 2008). There is a single N-terminal immunoglobulin variable region (IgV)-like domain, a transmembrane domain, and a cytoplasmic tail containing C-terminal immunoreceptor tyrosine-based switch motif (ITSM) sequence TEYATI and N-terminal immunoreceptor tyrosine-based inhibition motif (ITIM) sequence VDYGEL (Boussiotis, 2016). The inhibitory function of PD-1 signaling depends on the Y248 of ITSM but not the Y223 of ITIM (Patsoukis et al., 2020). Real-time evens of live-cell imaging during PD-1 ligation reveals that SHP-2 interacts with PD-1, and the ITSM of PD-1 serves as a docking site for SHP-2 (Chemnitz et al., 2004; Sheppard et al., 2004; Yokosuka et al., 2012). The recruitment of SHP-2 to PD-1 Y248 after PD-1 ligation is required for PD-1-mediated inhibitory function.

2.1. Effects of PD-1 on TCR-mediated signaling

The mechanism of PD-1 antagonizing TCR signaling has been heavily investigated. Upon PD-1 ligation, the ITSM of PD-1 is phosphorylated by the TCR proximal Src family kinase, subsequently recruiting and activating the allosteric dephosphorylating enzyme SHP-2 within the PD-1 complex (Patsoukis et al., 2020; Yokosuka et al., 2012). The activated SHP-2 mediates dephosphorylation of TCR proximal signaling molecules, including Lck and ZAP-70, leading to the inhibition of downstream events including the PI3K-AKT and Ras-MEK-ERK pathways (Parry et al., 2005; Patsoukis et al., 2012; Sheppard et al., 2004). It has been demonstrated that PD-1 signaling does not induce global signal inhibition, for example, the activation of p38 MAPK is not suppressed by PD-1 signaling (Patsoukis et al., 2012). PD-1 ligation induces expression of certain transcription factors including the AP-1 family member BATF. T cell proliferation and cytokine secretion are impaired when BATF expression is enhanced (Quigley et al., 2010). Unbalanced activation of signaling pathways alters T cell biochemical events, signal transduction, gene transcription, and epigenetic programs, resulting in inhibition of T cell function (Fig. 1). In addition, T cell functions have different sensitivities to PD-1 levels, which is consistent with differential effects of the PD-1 signaling pathway. High levels of PD-1 and ligation lead to the inhibition of MIP1β production, while lower levels are adequate for blocking calcium flux and the production of IFN-γ. Very low levels of PD-1 are sufficient to inhibit the expression of interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α), as well as to suppress T cell expansion (Wei et al., 2013).

Fig. 1.

Fig. 1

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Effects of PD-1 axis in T cells.

Upon PD-1 engagement, the ITSM of PD-1 is phosphorylated, subsequently recruiting and activating the SHP-2 within the PD-1 complex. The activated SHP-2 mediates dephosphorylation of TCR proximal signaling molecules, including Lck and ZAP-70, T cell costimulatory receptor CD28, and common cytokine receptor γ chain (γc). Activation of the PI3K-AKT and Ras-MEK-ERK pathways are inhibited. CD28−and γc family cytokine-triggered immune activation is impaired. In contrast, the expression of transcription factor BATF is up-regulated, which subsequently induces transcription of the E3 ubiquitin ligase MARCH5. MARCH5 is recruited to γc and mediates its K27-linked polyubiquitination and lysosomal degradation. The imbalanced activation of signaling pathways alters cell-cycle progression, gene transcription and epigenetic programs in T cells, resulting in a net outcome of T cell quiescence and immune suppression.

2.2. Effects of PD-1 on γc family cytokine-triggered signaling

γc (also called CD132) is a component of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 (Leonard et al., 2019a; Rochman et al., 2009). γc is constitutively expressed on different immune cells. It has been reported that X-linked severe combined immunodeficiency is associated with mutation of IL2RG which encodes γc (Leonard et al., 2019a; Noguchi et al., 1993). Cytokines of the γc family are considered as pleiotropic regulators in both innate and adaptive immune responses. For example, they promote either survival or death of immune cells depending on the context, and modulate differentiation of precursor immune cells into more terminally differentiated cells (Overwijk et al., 2021; Sakaguchi et al., 2008). Some of the γc family cytokines, such as IL-2, IL-15 and IL-21, have been used as immune-enhancing agents due to their functions in regulating T, NK and another immune cell (Leonard et al., 2019b). γc family cytokine activates regulatory T cells and effector T cells through three signaling pathways (JAK-STAT, Ras–MEK–ERK pathway, and PI3K-Akt pathways) (Leonard et al., 2019b; Overwijk et al., 2021). Previous studies have shown that PD-1 mediates inhibition of PI3K-AKT pathway and Ras-MEK-ERK pathway (Parry et al., 2005; Patsoukis et al., 2012; Sheppard et al., 2004). PD-1 signal can also antagonize γc family cytokine-mediated immune activation by directly targeting γc (Liu et al., 2023).

The level of γc in CD8+ T cells is negatively correlated with PD-1 activity. PD-1 ligation promotes lysosomal degradation of γc. MARCH5 is the E3 ubiquitin ligase of γc, which is induced by PD-L1 stimulation. MARCH5-deficiency up-regulates the level of γc and blocks PD-1 ligation-induced K27-linked polyubiquitination and lysosomal degradation of γc. Mechanistically, the transcription factor BATF induced by PD-L1 ligation binds to the promoter of MARCH5 gene, leading to its transcription. PD-L1-induced up-regulation of MARCH5 mRNA and down-regulation of γc protein level is inhibited in BATF-deficient cells. These studies suggest that PD-1 ligation results in BATF-dependent transcriptional induction of the E3 ubiquitin ligase MARCH5, leading to K27-linked polyubiquitination and lysosomal degradation of γc (Liu et al., 2023).

PD-1-induced inhibition of γc-mediated signaling and immune activation is also regulated by SHP-2 (Liu et al., 2023). PD-1 ligation triggers clustering of PD-1 with dynamic TCR microclusters which is necessary for the recruitment of SHP-2 and accumulates at the signaling central supramolecular activation cluster (c-SMAC) (Boussiotis, 2016; Patsoukis et al., 2020; Xu et al., 2020). The activated SHP-2 dephosphorylates TCR proximal signaling molecules. After clustering, PD-1 is partially segregated from TCR, but constitutively interacts with SHP-2, suggesting that PD-1-associated SHP-2 has the potential to mediate dephosphorylation of non TCR-associated molecules (Hui et al., 2017; Xu et al., 2020; Yokosuka et al., 2012). Previous studies have demonstrated that T cell costimulatory receptor CD28 is a target for PD-1-mediated inhibition, which is not a TCR-associated component (Hui et al., 2017). A recent study has also shown that PD-1 ligation-triggered SHP-2 activation induces dephosphorylation of γcY357, resulting in desensitization of γc-mediated signaling and immune activation (Liu et al., 2023). SHP-2-deficency impairs PD-1 ligation-induced γcY357 dephosphorylation and increases the γc family cytokine-induced phosphorylation of γcY357.

These results point to a model on the regulatory mechanisms of γc stability and activity by PD-1 signaling (Liu et al., 2023). PD-1 ligation promotes the interaction between SHP-2 and γc. The activated SHP-2 dephosphorylates γc at Y357, leading to its inactivation and unresponsiveness to γc family cytokines. On the other hand, PD-1 signaling triggers the transcription factor BATF, which subsequently induces transcription of the E3 ubiquitin ligase MARCH5. MARCH5 is recruited to γc and mediates its K27-linked polyubiquitination at K315 and lysosomal degradation (Fig. 1). PD-1-triggered SHP-2-mediated dephosphorylation of γc occurs in minutes, whereas PD-1-triggered induction of MARCH5 and degradation of γc is obvious one day after PD-1 ligation. Thus, it has been proposed that PD-1 signal inhibits γc family cytokine-triggered immune activation via the two mechanisms in a temporal manner (Liu et al., 2023).

3. PD-1/PD-L1 blockade in cancer

A key mechanism by which tumor cell restricts host immune responses is the upregulation of PD-L1 in tumor microenvironment (TME) and its interaction with PD-1 on tumor-infiltrating CD8+ T cells (Chen et al., 2018; Waldman et al., 2020). PD-L1 can be induced through various mechanisms, such as activation of PI3K-AKT pathways and inflammatory cytokines, of which IFN-γ is the most effective (Akbay et al., 2013; Sun et al., 2018). These cytokines can induce PD-L1 expression not only on tumor cells, but also on dendritic cells (DCs) and macrophages in TME (Zou & Chen, 2008). Tumor-infiltrating T cells that recognize tumor antigens are the producers of IFN-γ, suggesting that the immune system-generated anti-tumor immune response also initiates the immunosuppressive pathway by inducing PD-L1 expression (Saibil & Ohashi, 2020). Since PD-1 is expressed on activated T cells, the inhibition function of PD-1 is exerted after T cells recognize tumor antigens and produce tumor-specific responses, resulting in selective inhibition of cytotoxic T cell function (Waldman et al., 2020). In such contexts, targeted blockade therapy of the PD-1 axis induces the rejuvenation and expansion of tumor-infiltrating CD8+ T cells, thereby promoting effective tumor elimination (Rizvi et al., 2015).

Numerous preclinical efforts have investigated whether blocking the PD-1/PD-L1 pathway can be used for cancer therapy. Overexpression of PD-L1 in cancer cells inhibits the cytotoxic anti-tumor response of CD8+ T cells, whereas tumor rejection is achieved in mice with PD-1 dysfunction (Hirano et al., 2005; Iwai et al., 2002). PD-1 blockade therapy inhibits the growth of myeloma cells transplanted from syngeneic animals, while overexpression of PD-L1 shows the opposite result (Iwai et al., 2002). PD-1 axis-blocking antibody therapy enhances the killing effect of CD8+ T cells on tumor cells (Hirano et al., 2005; Iwai et al., 2002; Strome et al., 2003). In mouse B16 melanoma and CT26 colon carcinoma models, inhibition of the PD-1 axis not only enhances anti-tumor immunity, but also limits hematogenous spread of tumor metastases (Iwai et al., 2005). In addition to the function of the PD-1 axis in cancer therapy, multiple clinical studies have also performed a negative correlation between the expression of PD-1 axis proteins and tumor prognosis (Hamanishi et al., 2007; Thompson et al., 2007).

However, not all cancer patients benefit from PD-1 monotherapy. Clinically, the effective response rate of PD-1 blockade therapy for cancer is only 10%–20% (Sharma et al., 2023; Waldman et al., 2020). The primary reason for this limited response is the low tumor tissue immune scores observed in most patients (Bonaventura et al., 2019). Consequently, there is considerable interest in developing combination therapies aimed at enhancing the overall response rate of cancer patients and eliciting more complete and lasting responses. Immunotherapy, such as CTLA-4 blockade, 4-1BB/OX40 agonists, MITA agonists, and cytokines, which primarily function to boost immunogenicity by stimulating immune cells often induces the expression of PD-1 on T cells (Kennedy & Salama, 2020; Riley et al., 2019). Therefore, combination immunotherapy for cancer based on PD-1 axis blockade has exhibited considerable promise. Examples include dual immune checkpoint blockade, co-stimulatory molecule agonists combined with PD-1 blockade, MITA agonists combined with PD-1 blockade, and cytokines combined with PD-1 blockade (Bommareddy et al., 2018; Yap et al., 2021).

4. Cancer combination therapy with PD-1 blockade and IL-2

PD-1 blockade plus IL-2 is a promising combination, and several clinical trials are underway (Leonard et al., 2019b; Overwijk et al., 2021; Pol et al., 2020). Due to its ability to stimulate proliferation of cytotoxic T lymphocytes and NK cells, IL-2 was used as a cancer therapeutic agent shortly after its discovery (Boyman & Sprent, 2012; Overwijk et al., 2021). However, the therapeutic effects depend on high-dose of IL-2 in certain cancer patients, and systemic toxicity limits its widespread application. (Boyman & Sprent, 2012; Krieg et al., 2010; Marabondo & Kaufman, 2017). Compared with PD-1 blockade or IL-2 monotherapy, PD-1 blockade and IL-2 combination therapy significantly improve anti-tumor efficacy and have been widely used in immunotherapy for various cancers (Overwijk et al., 2021). The combined immunotherapy eliminates the inhibitory brake of PD-1 while providing a stimulatory signal for cytotoxic T lymphocytes by IL-2. Previous studies have indicated that the combination immunotherapy impacts the CD8+ T cell exhaustion program, with bispecific PD1-IL2v and anti-PD-L1 showing potential in overcoming tumor immunity resistance by enhancing stem-like tumor-reactive CD8+ T cells and reprogramming macrophages (Hashimoto et al., 2022; Tichet et al., 2023).

Recent studies have demonstrated that PD-1 signaling down-regulates the level of γc, which impairs the cytokines of γc family-induced signaling and CD8+ T cell activation in the TME (Liu et al., 2023). PD-1 blockade eliminates the inhibition of γc, thereby restoring the responses of CD8+ T cells to the γc family cytokines and leading to the synergistic effects of combination immunotherapy of PD-1 blockade and IL-2 (Fig. 2). The studies also show that MARCH5 is a potential target for cancer immunotherapy. MARCH5-deficiency suppresses tumor growth, and promotes the anti-tumor effects of IL-2 as well as its combination with PD-1 blocking antibody in mice (Liu et al., 2023).

Fig. 2.

Fig. 2

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Mechanisms for the synergistic effects of PD-1 blockade plus IL-2.

In TME, the high activity of PD-1signaling antagonizes γc family cytokines-triggered signaling and immune activation (left). PD-1 blockade eliminates the inhibition of γc, thereby restoring the responses of CD8+ T cells to the γc family cytokines and leading to the synergistic effects of combination immunotherapy of PD-1 blockade and IL-2 (middle). Administration of Pitavastatin Calcium (PC) increases the level of γc and leads to improved efficacies of cancer immunotherapy by PD-1 blockade plus IL-2 (right).

Screens of a panel of Food and Drug Administration-approved drugs identifies Pitavastatin Calcium (PC) as an inhibitor of MARCH5 (Liu et al., 2023). PC is a unique lipophilic statin and potent inhibitor of HMG-CoA reductase (Sahebkar et al., 2021). Only PC but not other HMG-CoA reductase inhibitors treatment increases the level of γc in tumor-infiltrating lymphocytes and has a synergistic effect with IL-2 on tumor suppression, suggesting that PC promotes antitumor immunity via its inhibition of MARCH5 but not HMG-CoA reductase (Fig. 2). The studies also show that administration of MARCH5 inhibitor leads to improved efficacies of cancer immunotherapy by PD-1 blockade plus IL-2 (Liu et al., 2023).

5. Conclusion

In conclusion, PD-1 is a key co-inhibitory receptor that regulates the functions of T cells. It plays critical roles in maintaining self-tolerance under physiological and pathological conditions to being used by tumor cells for immune escape. Advancing knowledge of the PD-1 axis-induced signaling effect is helpful to reveal the molecular mechanism of PD-1 associated inhibition in diseases and elucidate the potential factors for the synergistic effects observed in PD-1 blockade-related combination therapy. A deeper understanding of such knowledge will also provide molecular targets and theoretical basis to inform the development of combination therapies targeting PD-1 and its downstream effectors. The future directions of combination immunotherapy should also be based on basic and mechanistic research, so as to develop more effective and less toxic treatment strategies.

Declaration of competing interest

The authors declare no competing interests.

Acknowledgements

This work was supported by grants from the State Key R&D Program of China (2022YFA1304900), the National Natural Science Foundation of China (32070775 and 32300758), the CAMS Innovation Fund for Medical Sciences (2019-I2M-5–071), the Major Scientific and Technological Project of Hubei Province (2022ACA005), the Fundamental Research Funds for the Central Universities (2042022dx0003), and the China Postdoctoral Science Foundation (2022TQ0236, 2023M732694).

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