Cross-talk between TNF-α and IFN-γ signaling in induction of B7-H1 expression in hepatocellular carcinoma cells

Qin

et al. 2020

Preprint

24Programmed death ligand 1 (PD-L1) has been recently shown to be a major 25 obstacle to antiviral immunity by binding to its receptor programmed death 1 (PD-1) 26 on specific IFN-γ producing T cells in chronic hepatitis B. Currently, IFN-α is widely 27 used to treat hepatitis B virus(HBV)infection, but its antiviral effect vary greatly 28 and the mechanism is not totally clear. We found that IFN-α/γ induced a marked 29 increase of PD-L1 expression in hepatocytes. Signal and activators of transcription 30 ( Stat1) was then identified as a major transcription factor involved in 31 IFN-α/γ-mediated PD-L1 elevation both in vitro and in mice. Blockage of the 32 PD-L1/PD-1 interaction by a specific mAb greatly enhanced HBV-specific T cell 33 activity by the gp96 adjuvanted therapeutic vaccine, and promoted HBV clearance in 34 HBV transgenic mice. Our results demonstrate the IFN-α/γ-Stat1-PD-L1 axis plays an 35 important role in mediating T cell hyporesponsiveness and inactivating 36 liver-infiltrating T cells in the hepatic microenvironment. These data raise further 37 potential interest in enhancing the anti-HBV efficacy of IFN-α and therapeutic 38 vaccines. 39 40 42 hepatitis B virus (HBV). Ultimate HBV clearance requires the coordination of the 43 potent T cell immune response and effective humoral immunity. However, -3 -44 HBV-specific T cell response, which plays a vital role in HBV clearance, is severely 45 impaired in chronic hepatitis B (CHB) patients, leading to long-term immune 46 tolerance [1, 2]. Several mechanisms may contribute to HBV-specific T cell tolerance 47 and exhaustion, including upregulation of co-inhibitory molecules such as 48 programmed death 1 (PD-1), T-cell immunoglobulin and mucin domain-49 containing molecule 3 (TIM-3), T-cell immunoglobulin and ITIM domain 50 (TIGIT), lymphocyte-activation gene 3 (LAG3), immunosuppressive prostaglandin 51 E2 (PGE2) receptors, cytotoxic T-lymphocyte antigen 4 (CTLA-4), and proapoptotic 52 protein Bcl2-interacting mediator (Bim) on HBV-specific CD8 + T cells, as well as on 53 CD4+ T cells and NK cells. [3-5]. Additionally, regulatory T cells and suppressive 54 cytokines also contribute to virus-specific T cell failure [6]. 55 Among the co-expressed inhibitory receptors on T cells, programmed death 56 ligand 1 (PD-L1) plays a critical role in impaired T cell immune responses. Of note, 57 its ligand PD-L1, a 40 kDa transmembrane protein, is constitutively expressed on 58 liver DCs, Kupffer cells, stellate cells, liver sinusoidal endothelial cells, and 59 hepatocytes. Binding of PD-L1 to PD-1 leads to T cell dysfunction by inhibiting T 60 cell activation, causing T cell exhaustion, anergy, and T cell apoptosis, as well as by 61 inducing Treg differentiation [7-11]. In addition, elevated PD-L1 levels in liver were 62 observed in chronic necroinflammatory liver diseases and autoimmune hepatitis [12, 63 13]. These indicate the immune regulatory function of the liver microenvironment that 64 may lead to T cell tolerance. 65 As an first-line treatment option, ...

Section: Introductionmentioning

confidence: 99%

PD-L1 upregulation by IFN-α/γ-mediated Stat1 suppresses anti-HBV T cell response

Qin

et al. 2020

Preprint

“…3A and Table ). Previous studies [30] have confirmed that the IFN‐γ pathway is one of the key pathways to induce PD‐L1 expression. TGF‐β plays an important role in promoting tumor immune escape and immunotherapy resistance [24,31].…”

Section: Resultsmentioning

confidence: 86%

Prevalence of PRKDC mutations and association with response to immune checkpoint inhibitors in solid tumors

Chen

Guan³

et al. 2020

Molecular Oncology

Predictive biomarkers of response to immune checkpoint inhibitors (ICI) help to identify cancer patients who will benefit from immunotherapy. Protein kinase, DNA‐activated, catalytic subunit (PRKDC) is an important gene for DNA double‐strand break (DSB) repair and central T‐cell tolerance. We aimed to investigate the association between PRKDC mutations and tumor mutation burden (TMB), tumor microenvironment (TME), and response to ICI. Whole‐exome sequencing data of 4023 solid tumor samples from the Cancer Genome Atlas (TCGA) and panel‐based sequencing data of 3877 solid tumor samples from Geneplus‐Beijing, China, were used to analyze the TMB. The mRNA expression data of 3541 solid tumor samples from TCGA were used to explore the effect of PRKDC mutations on the TME. Four ICI‐treated cohorts were analyzed for verifying the correlation between PRKDC mutations and the response to ICI. In both the TCGA and Geneplus datasets, we found that the TMB in PRKDC mutation samples was significantly higher than in PRKDC wild‐type samples (P < 0.05 and P < 0.0001, respectively). Further, TCGA datasets showed that PRKDC mutation samples were associated with a significantly increased expression of CD8+ T cells, NK cells, immune checkpoint, chemokines, etc. compared to PRKDC wild‐type samples (P < 0.05). In ICI‐treated cohorts, we also found the PRKDC mutations were associated with increased survival (median PFS, not reached vs. 6.8 months, HR, 0.2893; 95% CI, 0.1255–0.6672; P = 0.0650, Hellmann cohort; median OS, 1184 days vs. 250 days, HR, 0.5126; 95% CI, 0.2715–0.9679; P = 0.1020, Allen cohort), and the increase was significant in multivariate analysis (HR, 0.361; 95% CI, 0.155–0.841; P = 0.018, Allen cohort; HR, 0.240 95% CI, 0.058–0.998; P = 0.050, Hellmann cohort). In summary, we found that PRKDC mutation often appeared to co‐exist with deficiency in some other DNA damage repair mechanism and is nonetheless one of the important factors associated with increased TMB, inflamed TME, and better response to ICI.

“…TNF-α is reported to synergistically act with IFN-γ to induce PD-L1 expression at both mRNA and protein levels. IFN-γ enhances the resistance of the adaptive immune response by PD-L1 induction in hepatocellular carcinoma cells which upregulate the expression of IFN-γ receptors [41]. PD-L1 is expressed not only in all hematopoietic cells but also in many non-hematopoietic cell types, such as endothelial and epithelial cells [42,43].…”

Section: Immune Checkpoint Inhibitors and Reagents For Side-effect Rementioning

confidence: 99%

Humanized Mice as an Effective Evaluation System for Peptide Vaccines and Immune Checkpoint Inhibitors

Kametani

Ohno

Ohshima

et al. 2019

IJMS

Peptide vaccination was developed for the prevention and therapy of acute and chronic infectious diseases and cancer. However, vaccine development is challenging, because the patient immune system requires the appropriate human leukocyte antigen (HLA) recognition with the peptide. Moreover, antigens sometimes induce a low response, even if the peptide is presented by antigen-presenting cells and T cells recognize it. This is because the patient immunity is dampened or restricted by environmental factors. Even if the immune system responds appropriately, newly-developed immune checkpoint inhibitors (ICIs), which are used to increase the immune response against cancer, make the immune environment more complex. The ICIs may activate T cells, although the ratio of responsive patients is not high. However, the vaccine may induce some immune adverse effects in the presence of ICIs. Therefore, a system is needed to predict such risks. Humanized mouse systems possessing human immune cells have been developed to examine human immunity in vivo. One of the systems which uses transplanted human peripheral blood mononuclear cells (PBMCs) may become a new diagnosis strategy. Various humanized mouse systems are being developed and will become good tools for the prediction of antibody response and immune adverse effects.