TABLE 3.
The role of immune checkpoints in virus infection diseases.
| Associated immune checkpoints | Associated virus | Associated diseases | Related immune cells or other cells | Influence on efficacy | Mechanism | PMID |
|---|---|---|---|---|---|---|
| PD-1 | HBV | Acute or chronic HBV infection disease | HBsAg-specific B cell unable to mature into Ab-secreting cells and displayed increased expression of CD21lo and PD-1 | Anti-PD-1 antibodies could partially restore HBsAg-specific B-cell maturation | HBV infection has a marked impact on global and HBV-specific humoral immunity, yet HBsAg-specific B cells are amenable to a partial rescue by B-cell maturing cytokines and PD-1 blockade | 30084841 |
| PD-1 | HCV | Chronic HCV-infected chimpanzees | Restoring intrahepatic CD4+ and CD8+ T-cell immunity | Significant reduction in HCV viremia in responder animal | Successful PD-1 blockade likely requires a critical threshold of preexisting virus-specific T cells in liver and warrants consideration of therapeutic vaccination strategies in combination with PD-1 blockade to broaden narrow responses | 23980172 |
| PD-1 | HIV | HIV-infected patients | Increasing CD8+ T cells in patients with chronic HIV infection | Cof blocking CD39/adenosine and PD-1 signaling showed a synergic effect in restoring CD8+ T-cell function (secrete functional cytokines and kill autologous reservoir cells) in vitro | Combined blockade of CD39/adenosine and PD-1 signaling in vitro may exert a synergistic effect in restoring CD8+ T-cell function in HIV-1-infected patients | 34177939 |
| PD-1 | CMV | Chronic CMV infection after renal transplantation | Higher positive rate of PD-1 in CMV-specific CD4+ T cell from viremic transplant recipients, loss of IL-2 production | Blockade of PD-1/PD-L1 could reverse functional anergy of CMV-specific CD4+ T cell and increase 10-fold proliferation in CMV-specific CD4+ T cell | Expression of PD-1 defines a reversible defect of CMV-specific CD4 T cells that are associated with viremia, and blocking PD-1 signaling may provide a potential target for enhancing the function of exhausted T cells in chronic CMV infection | 18510628 |
| PD-1 | HPV | HPV associated squamous cell carcinoma of the head and neck | Cancer cells | Pembrolizumab was tolerated with 17% grade 3-4 irAEs; the overall response was 25% in HPV-positive patients | Greater antitumor activity was recorded in patients with squamous cell carcinoma tumors of the head and neck that expressed higher levels of PD-L1 and interferon-γ-related genes. Thus, pembrolizumab might represent a new treatment approach for patients with squamous cell carcinoma of the head and neck | 27247226 |
| CTLA-4 | LCMV | Mice chronically infected with LCMV | Virus-specific CD8+ T cell | Blockade of the CTLA-4 had no effect on either T-cell function or viral control | Inhibition mediated by PD-1 requires close proximity of PD-1 to the site of TCR engagement and does not signal in the absence of a TCR signal. Following crosslinking by PD-1 ligand, the immunoreceptor tyrosine-based switch motif (ITSM) in the cytoplasmic domain of PD-1 is phosphorylated and recruits the phosphatases SHP-1 and SHP-2. These phosphatases act on proximal signaling kinases of the TCR pathway, reducing the TCR signal and leading to diminished T-cell activation and cytokine production. Therefore, under conditions of persistent antigen, T cells may modulate their responsiveness by upregulating inhibitory receptors such as PD-1 that attenuate TCR signaling | 16382236 |
| CTLA-4 | HBV | Chronic HBV infection | CTLA-4 is upregulated on HBV-specific CD8+ T cells with the highest level of Bim protein | Blocking CTLA-4 can increase the expansion of IFN-gamma producing HBV-specific CD8+ T cells | CTLA-4 is expressed by HBV-specific CD8+ T cells with high levels of Bim and helps to drive this proapoptotic phenotype | 21360567 |
| CTLA-4 | HCV | Patients with hepatocellular carcinoma and chronic HCV infection | Cancer cells | Anti-CTLA-4 showed a good safety profile; no patients needed steroids due to severe irAEs; disease control rate was 76.4% | HCV-specific CD8+ T cells that are exhausted express various inhibitory receptors, including CTLA-4 that acts synergistically with the programmed cell death-1 receptor (PD-1) to enforce their exhaustion state. Moreover, CTLA-4 is preferentially upregulated in PD-1+ T cells from the liver of chronically HCV-infected patients. It seems possible that the revival of antiviral T-cell immunity in patients with long-lasting chronic HCV infection following tremelimumab therapy may result from increased CD4+ T cell help and recovery of CD8+ T-cell exhaustion | 23466307 |
| CTLA-4 | HIV | HIV-infected patients | No pattern was noted regarding the change from baseline in CD4 or CD8 T cells | No serious adverse events or dose-limiting toxicities and ipilimumab were associated with variations in HIV RNA | Ipilimumab treatment of an HIV-infected patient on antiretroviral therapy increased CD4+ T cells, predominantly total memory and effector-memory cells, postinfusion along with transient increases in CD8+ T cells without change in cell activation. Furthermore, ipilimumab increased cell-associated unspliced HIV RNA and a subsequent decline in plasma HIV RNA | 29879143 |
| CTLA-4 | HIV | HIV-infected patients | CTLA-4 was upregulated in HIV-specific CD4+ T cells but not CD8+ T cells | CTLA-4 expression correlated positively with disease progression and negatively with the capacity of CD4+ T cells to produce interleukin 2 in response to viral antigen. In vitro blockade of CTLA-4 augmented HIV-specific CD4+ T-cell function | CTLA-4 ligation can suppress effector T-cell functions both directly through CTLA-4 expressed on effector cells and indirectly through CTLA-4 expressed on CD4+CD25+ Treg cells. A CTLA-4-mediated effect of Treg cells can probably occur in vivo both by direct T-cell-T-cell contact and indirectly by induction of indoleamine-2,3-dioxygenase in dendritic cells | 17906628 |
| PD-1/CTLA-4 | HAV | HAV-associated hepatitis | Isolated PBMC, PD-1, and CTLA-4 on T cells were measured by flow cytometry | Significantly higher expression of PD-1 and CTLA-4 on T cells consistent with a viral-protective effect of PD-1 and CTLA-4, thereby preventing the destruction of virus-infected hepatocytes in AHA | The changing expression of PD-1 and CTLA-4 during the symptomatic and recovery phases of AHA points to the protective effects of these inhibitory molecules, perhaps by suppressing the activity of cytotoxic T cells, thereby preventing the induced fulminant destruction of HAV-infected hepatocytes | 26347518 |
| PD-1/CTLA-4 | EBV | Intraperitoneally inject EBV-infected human cord blood into NSG mice | Increasing EBV-specific T-cell response and enhancing tumor infiltration by CD4+ and CD8+ T cells | Combination of PD-1/CTLA-4 blockade reduced the size of lymphoma, decreased the number of both latently and lytically EBV-infected B cells | PD-1/CTLA-4 blockade markedly increases EBV-specific T-cell responses and is associated with enhanced tumor infiltration by CD4+ and CD8+ T cells | 27186886 |
| PD-1/CTLA-4 | SIV | SIV-infected long-term antiretroviral therapy-treated rhesus macaques | Decreasing total and intact SIV-DNA in CD4+ T cells and B-cell follicles | Inducing robust latency reversal and reducing total levels of integrated virus. No enhanced SIV-specific CD8+ T-cell responses or viral control | Dual CTLA-4/PD-1 blockade produced a significant reduction in cell-associated SIV-DNA within LN CD4+ TEM, the CD4+ T-cell subpopulation most activated from combined treatment. Importantly, in situ hybridization assays demonstrated a significant reduction in the number of vRNA+ and vDNA + cells following dual CTLA-4/PD-1 blockade in the LN, including in the BCF | 32284611 |
| LAG-3 | HIV | AIDS | T cell | High viral load, faster disease progression, and rapid return of viremia following treatment interruption | Although mechanisms and functions of LAG-3 remain controversial, LAG-3 clearly inhibits immune responses. If LAG-3 blockade improves immune function during HIV infection, it could help deplete the HIV reservoir by reversing latency and restoring immunity of exhausted cells | 30653605 |
| LAG-3 | HBV | Hepatocellular carcinoma | CD8 (+) T cells | Acting as a suppressor of HBV-specific | Since LAG-3 is an inhibitory molecule that plays a downregulatory role on T-cell responses, we found the correlation between LAG-3 expression and HBV-specific CD8+ T cells dysfunction | 23261718 |
| LAG-3 | HPV | OPSCC | CD8 (+) T cells | HPV-related OPSCC might be more susceptible to single or combined anti-LAG-3 antibody therapy than HPV-negative OPSCC patients | Possible reasons for this may be the interrelationship of multiple components in the tumor immune microenvironment, as it has been reported that the coexpression of LAG-3 with other inhibitory molecules such as TIM-3 or PD-1 induces the exhaustion of immune cells, resulting in downregulated cytokine expression | 33396515 |
| LAG-3 | HCV | Follicular lymphoma | CD8 T cells | Inhibiting cell proliferation, cytotoxicity function, and cytokine production | LAG-3 expression could be substantially upregulated on CD4+ or CD8+ T cells by IL-12, a cytokine that has been shown to induce T-cell exhaustion and be increased in the serum of lymphoma patients. Furthermore, we found that blockade of both PD-1 and LAG-3 signaling enhanced the function of intratumoral CD8+ T cells resulting in increased IFN-γ and IL-2 production | 28977875 |
| LAG-3 | LCMV | Chronic viral infections | CD8 T cells | LAG-3 is continuously upregulated on LCMV-specific exhausted CD8 T cells; it alone does not significantly contribute to T-cell exhaustion | LAG-3 is upregulated on LCMV-specific exhausted CD8 T cells; it does not significantly contribute to T-cell exhaustion alone. To effectively interfere with T-cell exhaustion, it is very likely that several inhibitory receptors will have to be targeted simultaneously | 19880580 |
| IDO1 | HIV | HIV-1 infection | CD4+ T cells | IDO may represent a critical initiating event that results in inversion of the T(H)17/T (reg) balance and in the consequent maintenance of a chronic inflammatory state in progressive HIV disease | IDO1-dependent tryptophan catabolism may be an important link between immune activation and the gradual decline of immune function seen in progressive HIV infection | 20484731 |
| IDO1 | HPV16 | Head and neck squamous cell carcinomas | HPV16-specific CD8+ T cells | The HPV16 CTL epitopes identified in this study, in combination with blockade of HPV + HNSCC-specific PD-1/IDO-1 checkpoints, may be useful for targeted immunotherapy | Our findings implicate mechanisms of T-cell escape in HPV + HNSCC, wherein high tumoral HPV-antigen load results in high expression of immune dysfunction genes on tumor cells (e.g., IDO-1) and dysfunction of HPV-specific CTLs (e.g., E7; E2-CTLs). HPV + HNSCCs expressing IDO-1 might similarly be driven by HPV-specific-CTL infiltration in response to high tumoral HPV-antigen load | 30154146 |
| IDO1 | HPV | Chronic infection | Invariant natural killer T; T cell | Induction of IDO1 in HPV-infected skin contributes to evasion of host immunity | Inhibiting IDO activity using 1-methyl-DL-tryptophan (1-D/L-MT) promotes K14E7 skin graft rejection. Increased IDO1 expression and activity in K14E7 skin require IFN-g and invariant natural killer T (iNKT) cells, both of which have been shown to negatively regulate T-cell effector function and suppress K14E7 graft rejection. Furthermore, DCs from K14E7 skin express higher levels of IFN-g receptor (IFN-gR) than DCs from control skin | 23652797 |
| VISTA | HIV | AIDS | CD4+ and CD8+ T cells | Gal-9 and VISTA expression was associated with impaired T-cell effector functions | A dramatic reduction in the production of cytokines by T cells expressing PD-1, CD160, CD39, TIM-3, and VISTA. In contrast to other coinhibitory molecules, the pattern of cytokine production was not different between 2B4+ and 2B42 CD4+ T cells, and interestingly 2B4+ CD8+ T cells exhibited higher cytokine production capabilities compared with 2B42 CD8+ T cells | 32205423 |
| TIM-3 | HIV | AIDS | T cells | Blocking the TIM-3 signaling pathway restored proliferation and enhanced cytokine production in HIV-1-specific T cells | In progressive HIV-1 infection, TIM-3 expression was upregulated on HIV-1-specific CD8 + T cells. TIM-3-expressing T cells failed to produce cytokine or proliferate in response to antigen and exhibited impaired Stat5, Erk1/2, and p38 signaling. Blocking the TIM-3 signaling pathway restored proliferation and enhanced cytokine production in HIV-1-specific T cells | 19001139 |
| TIM-3 | HCV | HCV infection | HCV-specific CTLs | Blockade of either PD-1 or TIM-3 enhanced in vitro proliferation of HCV-specific CTLs to a similar extent, whereas cytotoxicity against a hepatocyte cell line that expressed cognate HCV epitopes was increased exclusively by TIM-3 blockade | Early accumulation of PD-1+TIM-3+ T cells is associated with functional impairment and consequently with the development of persistent HCV. The present study provides a basis for improving current therapies by simultaneous blockade of multiple inhibitory pathways that could result in additive efficacy without excessive toxicity | 21084749 |
| TIM-3 | LCMV | Chronic LCMV infection | CD8 T cell | Targeting both PD-1 and TIM-3 is an effective immune strategy for treating chronic viral infections | Whereas TIM-3 was only transiently expressed by CD8 T cells after acute infection, virus-specific CD8 T cells retained high TIM-3 expression throughout chronic infection. The majority (approximately 65–80%) of lymphocytic choriomeningitis virus-specific CD8 T cells in lymphoid and nonlymphoid organs coexpressed TIM-3 and PD-1. This coexpression of TIM-3 and PD-1 was associated with more severe CD8 T-cell exhaustion in terms of proliferation and secretion of effector cytokines such as IFN-γ, TNF-α, and IL-2. Interestingly, CD8 T cells expressing both inhibitory receptors also produced the suppressive cytokine IL-10. Most importantly, combined blockade of TIM-3 and PD-1 pathways in vivo synergistically improved CD8 T-cell responses and viral control in chronically infected mice | 20679213 |
| TIM-3 | Friend virus | Acute Friend virus-induced disease | CD8 T cell | Combined blockade of PD-1 and TIM-3 during the priming/differentiation phase rescued FV-specific CD8 (+) T cells from becoming terminally exhausted, resulting in improved CD8 (+) T-cell functionality and virus control | TIM-3 and CTLA-4 were recently found to be overexpressed on HIV- and hepatitis C virus-specific CD4+ and CD8+ T cells and to act to suppress effector functions of activated T cells. Upregulation of LAG-3 was also shown to correlate with the impaired effector functions and exhaustion of CD8+ T cells | 20351188 |
| TIM-3 | HBV | Chronic HBV infection | CD4+ and CD8+ T cells | Overexpression of TIM-3 is involved in disease progression of CHB and that TIM-3 may participate in skewing of Th1/Tc1 response, which contributes to the persistency of HBV infection | The expression of TIM-3 is upregulated on circulating CD4+ and CD8+ T cells in CHB patients. TIM-3 was highly expressed on T cells from AHB patients as well; however, its expression decreased dynamically in the convalescence phase. TIM-3 expression positively correlated with disease severity and negatively correlated with Th1/Tc1 response in CHB patients | 21392402 |