Expression Of Poliovirus Receptor Research Articles

Adaptive Design of Nanovesicles Overcoming Immunotherapeutic Limitations of Chemotherapeutic Drugs through Poliovirus Receptor Blockade.

Chemotherapy is currently a widely used treatment for cancer in clinical settings. Some chemotherapeutic drugs such as oxaliplatin (OXA) can cause tumor immunogenic cell death (ICD), activate immunity, and realize chemoimmunotherapy for tumors. However, the low degree of accumulation and immunosuppressive microenvironment in tumors limit the immunotherapeutic efficacy of these drugs. T cell immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor (PVR) is an inhibitory immune checkpoint pathway involved in mediating natural killer (NK) cell and T cell exhaustion in tumors. TIGIT expression is up-regulated in NK cells and CD8+ T cells during tumor development. Moreover, we first found that tumors upregulated PVR expression after OXA treatment in previous work. Here, we systematically analyzed the effects of OXA on the TIGIT/PVR pathway, further proving the effectiveness of the combination of OXA and TIGIT/PVR blocking combination. We developed engineered TIGIT-expressing cell membrane nanovesicles loaded with OXA (OXA@TIGIT MVs) for synergistic cancer therapy. OXA@TIGIT showed good efficacy in several cancer models, leading to tumor regression, effectively inhibiting tumor growth and prolonging mouse survival. Furthermore, the OXA@TIGIT MVs activate a strong tumor-specific immune response in the body, providing long-term (more than 2 months) protection from tumor reactivation in the B16F10 melanoma rechallenge mouse model.

ADAR-mediated RNA editing regulates PVR immune checkpoint in colorectal cancer

Recent studies have revealed that tumor immunotherapy resistance is influenced by ADAR-mediated RNA editing, but its targets remain unelucidated. Our current study identified the poliovirus receptor (PVR) oncogene, which encodes an immune checkpoint in colorectal cancer (CRC), as a potential target for RNA editing. We performed transcriptome sequencing analysis and experimental validation in two Chinese CRC cohorts. PVR and ADAR expressions significantly increased in CRC tumors and showed positive correlations in both cohorts, coupled with upregulated PVR RNA editing in CRC tumors. Manipulation of ADAR expression by over-expression or knockdown substantially changed PVR expression and RNA editing in HTC116 CRC cells. Luciferase reporter and actinomycin D assays further revealed that RNA editing in PVR 3′-UTR could upregulate PVR RNA expression, probably by increasing the RNA stability. By increasing PVR expression, ADAR-mediate RNA editing might contribute to tumor- and immune-related gene functions and pathways in CRC. Moreover, a signature combining PVR RNA editing and expression showed promising predictive performance in CRC diagnosis in both Chinese CRC cohorts. Our findings thus highlight the importance of ADAR-mediated RNA editing in PVR up-regulation in CRC tumors and provide new insight into the application of PVR RNA editing as a novel diagnostic biomarker for CRC.

Poliovirus receptor (PVR) mediates carboplatin-induced PD-L1 expression in non-small-cell lung cancer cells

Programmed death-ligand-1 (PD-L1) is an immune suppressor that inhibits T cell based immunity. Anti-PD-L1/PD-1 immunotherapy benefits those patients receiving platinum-based combinational chemotherapy. However, the underlying mechanism is still largely unknown. In this study, we found that carboplatin could induce PD-L1 expression in NSCLC H292, A549 and H1299 cells in a dose-dependent manner. mRNA sequencing and the subsequent validation assays found that carboplatin significantly induced PVR expression, which is considered as an immuno-adhesion molecule. Mechanistically, PVR knockdown significantly abrogated carboplatin-induced PD-L1 expression. Functionally, knockdown of PVR significantly reversed the CD3+ T cells proliferation inhibition caused by carboplatin increased PD-L1. Moreover, the carboplatin-induced PVR and subsequent up-regulation of PD-L1 might be mediated via the EGFR, PI3K/AKT, and ERK signaling pathways. Immunohistochemical staining results showed that the PD-L1 expression was positively associated with PVR expression in clinical NSCLC samples. Our study reveals a novel regulatory mechanism of PD-L1 expression, provides evidence that carboplatin inhibits tumor immune response by up-regulating PD-L1 expression and explains the rationale for combining platinum-based chemotherapy with PD-L1/PD-1 inhibitors.

Phase 1/2 study of tiragolumab and atezolizumab in patients with relapsed or refractory SMARCB1 or SMARCA4 deficient tumors.

TPS10066 Background: The SMARCB1/A4 gene products are core subunits of the SWItch/Sucrose Non-fermentable (SWI/SNF) chromatin remodeling complex. Tumors with defects in SWI/SNF are histologically distinct aggressive cancers occurring in children and young adults. SMARCB1/A4 deficient tumors, particularly rhabdoid tumors, poorly differentiated chordoma, epithelioid sarcoma, and medullary renal cell carcinoma, have immune cell infiltrates and programmed death ligand 1 (PD-L1) expression. Response to immune checkpoint inhibition (CI) has been observed in SMARCB1/A4 deficient tumors; however, responses are not durable. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a novel inhibitory receptor expressed on multiple immune cells. TIGIT inhibits T and NK cells by binding to its ligand poliovirus receptor (PVR) and Nectin2 on tumor cells and antigen-presenting cells. Utilizing RNAseq data, SMARCB1/A4 deficient tumors demonstrate high expression of PVR and Nectin2. Tiragolumab is an antibody to the TIGIT receptor. In patients with non-small cell lung cancer, tiragolumab with atezolizumab increased survival compared to atezolizumab alone. Thus, data suggest that SMARCB1/A4 deficient tumors are susceptible to CI; however, monotherapy is unlikely to achieve durable responses; the addition of tiragolumab may enhance response rates. Methods: This is a phase 1/2 trial of tiragolumab monotherapy and in combination with atezolizumab in patients ≥ 12 months of age with SMARCB1/A4 deficient tumors administered IV on Day 1 of 21-day cycles. Part A will evaluate the safety of tiragolumab monotherapy (300 mg if ≤ 15 kg; 420 mg if >15 to ≤ 40 kg; 600 mg if > 40 kg or ≥ 18 yrs) based on cycle 1 DLTs in up to 6 evaluable patients <18 yrs of age. Part B will estimate the antitumor activity of tiragolumab in combination with atezolizumab (15 mg/kg [max 1200 mg]) if < 18 yrs or 1200 mg if ≥ 18 yrs) in 6 histology-specific cohorts (renal medullary carcinoma, malignant rhabdoid tumor, atypical teratoid rhabdoid tumor, poorly differentiated carcinoma, epithelioid sarcoma, and other) Each cohort will be conducted using a 6+4 Simon’s two stage design. Up to 13 patients may enroll in each cohort allowing for inevaluable patients (maximum n=78). Enrollment of patients ≥ 18 yrs on Part B may occur concurrently with enrollment of patients < 18 yrs on Part A. If the pediatric dose of tiragolumab is deemed safe, patients <18 yrs old may be enrolled on Part B. Cycle 1 toxicities of the combination therapy will be monitored in Part B using a Bayesian Optimal Interval Design in patients < 12 yrs of age. The secondary objectives are to characterize pharmacokinetics/anti-drug antibody and estimating progression free survival, overall survival, and duration of response. Enrollment is open for all Pediatric Early Phase Clinical Trial Network sites. Clinical trial information: NCT05286801 .

CDK4/6 inhibitors and the pRB-E2F1 axis suppress PVR and PD-L1 expression in triple-negative breast cancer

Immune-checkpoint (IC) modulators like the poliovirus receptor (PVR) and programmed death ligand 1 (PD-L1) attenuate innate and adaptive immune responses and are potential therapeutic targets for diverse malignancies, including triple-negative breast cancer (TNBC). The retinoblastoma tumor suppressor, pRB, controls cell growth through E2F1-3 transcription factors, and its inactivation drives metastatic cancer, yet its effect on IC modulators is contentious. Here, we show that RB-loss and high E2F1/E2F2 signatures correlate with expression of PVR, CD274 (PD-L1 gene) and other IC modulators and that pRB represses whereas RB depletion and E2F1 induce PVR and CD274 in TNBC cells. Accordingly, the CDK4/6 inhibitor, palbociclib, suppresses both PVR and PD-L1 expression. Palbociclib also counteracts the effect of CDK4 on SPOP, leading to its depletion, but the overall effect of palbociclib is a net reduction in PD-L1 level. Hydrochloric acid, commonly used to solubilize palbociclib, counteracts its effect and induces PD-L1 expression. Remarkably, lactic acid, a by-product of glycolysis, also induces PD-L1 as well as PVR. Our results suggest a model in which CDK4/6 regulates PD-L1 turnover by promoting its transcription via pRB-E2F1 and degradation via SPOP and that the CDK4/6-pRB-E2F pathway couples cell proliferation with the induction of multiple innate and adaptive immunomodulators, with direct implications for cancer progression, anti-CDK4/6- and IC-therapies.

Abstract 6631: Association between poliovirus receptor (PVR) expression in tumor and exclusion of immune cells expressing T cell immunoreceptor with Ig and ITIM domain (TIGIT) from tumor area

Abstract Context: TIGIT has grown to be an increasingly important target for immunotherapy of cancer. However, it is unclear if there is an association between abundance of TIGIT expressing immune cells in tumor microenvironment and effectiveness of TIGIT-based intervention. This study utilizes an exploratory novel duplex immunohistochemical (IHC) assay to assess if the distribution patterns and/or the abundance of TIGIT-positive immune cells are related to the expression levels of TIGIT’s receptor PVR in tumor. Methods: Individual formalin-fixed, paraffin-embedded surgical resections and tissue microarray cores of 75 cervical, 84 esophageal, 79 non-small cell lung , and 81 small cell lung carcinoma specimens were stained using a duplex chromogenic IHC assay that detects PVR and TIGIT sequentially on a single slide. The slides were examined for (1) overall intensity and percentage of tumor staining positive for PVR, (2) percentage of tumor area occupied by TIGIT-expressing immune cells, and (3) distribution pattern of TIGIT-positive cells. For each specimen, overall PVR intensity was multiplied by percentage of tumor positive for PVR to generate the PVR Expression Score. Results: PVR and TIGIT staining at any intensity was widely observed in all four tumor types ranging from 91% to 100% of specimens positive for PVR and 77% to 100% of specimens positive for TIGIT. Little to no differences in the average percentages of PVR tumor positivity or TIGIT tumor area positivity were found among the four tumor types. However, individual tumor specimens differed widely in these two parameters. Among all 319 tumor specimens evaluated, the percentages of tumor expressing PVR at any intensity ranged from 0 to 100% with approximately 1/3 of the specimens having less than 50% and 3% showing no PVR expression. Percentages of tumor area occupied by TIGIT-positive cells ranged from 0% to 30% with approximately 40% of the specimens having less than 1%. Distribution patterns of TIGIT-expressing cells in each specimen was classified as peritumoral, intratumoral, or mixed. Specimens classified as peritumoral exhibited higher PVR Expression Scores than those classified as intratumoral. Specimens classified as having a mixed TIGIT-positive cell distribution pattern had an average PVR Expression Score that was intermediate between specimens having intratumoral and peritumoral TIGIT distribution patterns. Interestingly, no correlation was found between tumor PVR Expression Scores and abundance of TIGIT expressing cells in tumor area. Conclusion: The correlation between high tumor PVR expression levels and peritumoral distribution patterns of TIGIT-positive cells suggests PVR/TIGIT signaling pathway activation status could be important in infiltration of T cells into tumor parenchyma. Citation Format: Sara A. Moore, Julie Cheung, Aram B. Cholanians, June Clements, Jessica L. Baumann, Tsu-Shuen Tsao. Association between poliovirus receptor (PVR) expression in tumor and exclusion of immune cells expressing T cell immunoreceptor with Ig and ITIM domain (TIGIT) from tumor area [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6631.

Correlation of the TIGIT-PVR immune checkpoint axis with clinicopathological features in triple-negative breast cancer.

T cell immunoreceptor with Ig and ITIM domains (TIGIT) interacts with poliovirus receptor (PVR) to contribute to cancer immune escape. Recently, TIGIT and PVR have been identified as promising immunotherapy targets. Their gene expression is upregulated in many solid tumors, but their protein expression level is not well documented, particularly in triple negative breast cancer (TNBC), the breast cancer subtype that most benefit from immunotherapy. TIGIT and PVR expression levels were assessed by immunohistochemistry in 243 surgically resected localized TNBC and then their relationship with clinical-pathological features and clinical outcome was analyzed. TIGIT expression was observed in immune cells from the tumor microenvironment, whereas PVR was mainly expressed by tumor cells. High TIGIT expression was significantly associated with age (p=0.010), histological grade (p=0.014), non-lobular histology (p=0.024), adjuvant chemotherapy (p=0.006), and various immune cell populations (tumor infiltrating lymphocytes (TILs), CD3+, CD8+, PD-1+ cells; all p<0.0001), PD-L1+ tumor cells (p<0.0001), and PD-L1+ stromal cells (p=0.003). Infiltration by TIGIT+ cells tended to be higher in non-molecular apocrine tumors (p=0.088). PVR was significantly associated with histological grade (p<0.0001), the basal-like (p=0.003) and non-molecular apocrine phenotypes (p=0.039), high TILs infiltration (p=0.011), CD3+ (p=0.002), CD8+ (p=0.024) T cells, and PD-L1 expression in tumor (p=0.003) and stromal cells (p=0.001). In univariate analysis, only known prognostic factors (age, tumor size, lymph node status, adjuvant chemotherapy, TILs and CD3+ T-cell infiltrate) were significantly associated with relapse-free survival (RFS) and overall survival. High TIGIT and PVR expression levels tended to be associated with longer RFS (p=0.079 and 0.045, respectively). The analysis that included only non-molecular apocrine TNBC revealed longer RFS for tumors that strongly expressed TIGIT or PVR (p=0.025 for TIGIT and 0.032 for PVR). These results indicated that in TNBC, TIGIT+ cells can easily interact with PVR to exert their inhibitory effects. Their wide expression in TNBC and their association with other immune checkpoint components suggest the therapeutic interest of the TIGIT-PVR axis.

PVR-A Prognostic Biomarker Correlated with Immune Cell Infiltration in Hepatocellular Carcinoma.

The poliovirus receptor (PVR) is a member of the immunoglobulin superfamily (Ig SF) and is essential for the promotion of cancer cell proliferation and invasion. However, the correlation between PVR expression and prognosis as well as immune infiltration in hepatocellular carcinoma (HCC) remains unclear. The expression level of PVR was quantified using the Tumor and Tumor Immunity Evaluation Resource (TIMER) and Sangerbox. The Gene Expression Omnibus (GEO) database was used to validate the PVR expression. The receiver operating characteristic (ROC) curve was used to evaluate the feasibility of using PVR as a differentiating factor according to the area under curve (AUC) score. A PVR binding protein network was built using the STRING tool. An enrichment analysis using the R package clusterProfiler was used to explore the potential function of PVR. Immune infiltration analysis was calculated with ESTIMATE algorithms. We also assessed the correlation between PVR expression and immune infiltration by the single-sample Gene Set Enrichment Analysis (ssGSEA) method from the R package GSVA and TIMER database. The results showed that PVR was commonly overexpressed in multiple types of tumors including HCC. The data of GSE64041 confirmed the same result. The ROC curve suggested that PVR could be a potential diagnostic biomarker. Additionally, high mRNA expression of PVR in HCC was significantly correlated with poor overall survival (OS) and relapse free survival (RFS). Results also indicated correlations between PVR mRNA expression with the level of infiltration immune cells including B cells, CD8+ T cells, cytotoxic cells, DCs, CD56dim NK cells, pDCs, and Th2 cells. Furthermore, the PVR level was significantly correlated with immune markers for immunosuppressive cells in HCC. In conclusion, PVR might be an important regulator of tumor immune cell infiltration and a valuable prognostic biomarker in HCC. However, additional work is needed to fully elucidate the underlying mechanisms.

CD155 is a putative therapeutic target in medulloblastoma.

Medulloblastoma is the most common pediatric malignant brain tumor, consisting of four molecular subgroups (WNT, SHH, Group 3, Group 4) and 12 subtypes. Expression of the cell surface poliovirus receptor (PVR), CD155, is necessary for entry of the viral immunotherapeutic agent, PVSRIPO, a polio:rhinovirus chimera. CD155, physiologically expressed in the mononuclear phagocytic system, is widely expressed ectopically in solid tumors. The objective of this study is to elucidate CD155 expression as both a receptor for PVSRIPO and a therapeutic target in medulloblastoma. PVR mRNA expression was determined in several patient cohorts and human medulloblastoma cell lines. Patient samples were also analyzed for CD155 expression using immunohistochemistry and cell lines were analyzed using Western Blots. CD155 was blocked using a monoclonal antibody and cell viability, invasion, and migration were assessed. PVR mRNA expression was highest in the WNT subgroup and lowest in Group 4. PVR expression in the subgroups of medulloblastoma were similar to other pediatric brain and non-brain tumors. PVR expression was largely not associated with subgroup or subtype. Neither PVR protein expression intensity nor frequency were associated with overall survival. PVR expression was elevated in Group 3 patients with metastases but there was no difference in paired primary and metastatic medulloblastoma. Blocking PVR resulted in dose-dependent cell death, decreased invasion in vitro, and modestly inhibited cell migration. CD155 is expressed across medulloblastoma subgroups and subtypes. Blocking CD155 results in cell death and decreased cellular invasion. This study provides rationale for CD155-targeting agents including PVSRIPO and antibody-mediated blockade of CD155.

Human poliovirus receptor contributes to biliary atresia pathogenesis by exacerbating natural-killer-cell-mediated bile duct injury.

Natural killer (NK) cells play an important role in biliary atresia (BA) pathogenesis; human poliovirus receptor (PVR) is an important NK-cell modulator. Here, we explored the role of PVR in BA pathogenesis. Poliovirus receptor expression and NK cell-associated genes were detected in human BA samples and a rotavirus-induced BA mouse model using quantitative PCR and immunofluorescence staining. Chemically modified small interfering RNA silenced PVR expression in the BA model, and its effects on the population and function of intrahepatic NK cells were investigated using flow cytometry (FCM). The effects of PVR overexpression and knockdown on proliferation, apoptosis and NK-cell-mediated lysis of cultured human cholangiocytes were analysed using FCM and cell viability assays. Serum PVR, high-mobility group box 1 (HMGB1), and interleukin-1beta (IL-1beta) levels were measured in a cohort of 50 patients using ELISA. Poliovirus receptor expression was upregulated in the biliary epithelium of BA patients and BA model and was positively correlated with the population and activation of intrahepatic NK cells. Silencing of PVR expression impaired the cytotoxicity of NK cells, reduced inflammation and protected mice from rotavirus-induced BA. Activation of the TLR3-IRF3 signalling pathway induced PVR expression in cultured cholangiocytes. PVR overexpression promoted proliferation and inhibited the apoptosis of cholangiocytes but exacerbated NK cell-mediated cholangiocyte lysis. Serum PVR levels were elevated in BA patients and were positively correlated with HMGB1 and IL-1beta levels. Poliovirus receptor contributes to BA pathogenesis by regulating NK cell-mediated bile duct injury; PVR has the value as a biomarker of BA.

Prognostic Impact of Poliovirus Receptor Expression (PVR) (CD155) in Context to FLT3-ITD and NPM1 Mutation Status at Egyptian Acute Myeloid Leukemia

Background: Acute myeloid leukemia is a heterogeneous hematological malignancy with diversity in molecular, phenotypic and genetic alteration. Accurate assessment of prognosis is mandatory to reduce relapse, changing treatment related mortality, decision making for appropriate therapy protocols. Aim: A case control observational analytical study to assess the prognostic value of poliovirus (CD155) in acute myeloid leukemia and its significant in-patient stratification. Subject & Methods: 100 newly diagnosed de novo AML selected from oncology center, Mansoura University. Measurement of PVR (CD155) by multiparameter flow cytometry in addition to cytogenetic and molecular stratification. Results: Statistical stratification according to median cut off CD155 > 5.35. Higher expression was associated with an increased risk of death and relapse, LDH. While lower expression is associated with longer OS & DFS. Cox regression with univariate analysis revealed that LDH, molecular stratification, CD155 were significant risk factors for shorter OS, while positive expression of CD16, CD56 AML M3 were significantly associated with longer survival. Multivariate analysis revealed that CD155 was a significant risk factor for shorter OS. Conclusion: Variability in expression of CD155 in AML patients due to dual costimulatory and inhibitory function, high expression associated with tumor bulk and progression, short OS, increased relapse rate. Cox regression analysis shows its independent risk factor. It could be implemented in routine laboratory for risk stratification into low, high risk that needs more therapeutic modalities with new immunotherapy. In future could be targeted therapy such as PDL, CTLA-4 and open more therapeutic hope for those patients.

TIGIT blockade enhances NK cell activity against autologous HIV-1-infected CD4+ T cells.

ObjectivesDuring chronic human immunodeficiency virus (HIV)‐1 infection, inhibitory molecules upregulated on lymphocytes contribute to effector cell dysfunction and immune exhaustion. People living with HIV (PLWH) are at greater risk for age‐related morbidities, an issue magnified by human cytomegalovirus (CMV) coinfection. As CMV infection modifies natural killer (NK) cell properties and NK cells contribute to protection against HIV‐1 infection, we considered the role of T‐cell immunoreceptor with immunoglobulin and intracellular tyrosine inhibitory motif domains (TIGIT) in NK cell‐based HIV‐1 immunotherapy and elimination strategies.MethodsWe measured TIGIT expression on immune cell subsets of 95 PLWH and assessed its impact on NK cell function, including elimination of autologous CD4+ T cells infected through reactivation of endogenous HIV‐1.ResultsTIGIT was expressed on CD4+ T cells, CD8+ T cells and NK cells from PLWH. Although TIGIT levels on T cells correlated with HIV‐1 disease progression, the extent of TIGIT expression on NK cells more closely paralleled adaptation to CMV. TIGIT interacts with its predominant ligand, poliovirus receptor (PVR), to inhibit effector cell functions. Circulating CD4+ T cells from PLWH more frequently expressed PVR than HIV‐seronegative controls, and PVR expression was enriched in CD4+ T cells replicating HIV‐1 ex vivo. Treatment with anti‐TIGIT monoclonal antibodies increased NK cell HIV‐1‐specific antibody‐dependent cytotoxicity in vitro and ex vivo.ConclusionBlocking TIGIT may be an effective strategy to invigorate antibody‐dependent NK cell activity against HIV‐1 activated in cellular reservoirs for cure or treatment strategies.

Elevated Expression of Poliovirus Receptor in the Bile Duct Epithelium: A Possible Reason for the Pathogenesis of Biliary Atresia

Elevated Expression of Poliovirus Receptor in the Bile Duct Epithelium: A Possible Reason for the Pathogenesis of Biliary Atresia

Clinical significance of LSECtin and its association with PVR in non-small-cell lung cancer patients.

BackgroundLiver and lymph node sinusoidal endothelial cell C-type lectin (LSECtin) is one of the new generation immune checkpoint ligand molecules and plays an important role in the immune environment. Poliovirus receptor (PVR), as another immunosuppression-related molecule, is upregulated in various malignant tumors. However, the clinical value of LSECtin and the correlation of LSECtin with PVR in non-small-cell lung cancer (NSCLC) remain to be elucidated. In this study, a retrospective study was performed to address these issues.MethodsThis retrospective study included 98 patients with NSCLC. Immunohistochemistry (IHC) was used to detect the expression of LSECtin and PVR in the paraffin-embedded tumor tissue specimens. LSECtin was analyzed for associations with the survival rate and overall survival (OS) of the subjects. The mRNA expression of LSECtin and PVR was assessed using the expression data from The Cancer Genome Atlas (TCGA) database. Clinical characteristics, prognosis, and the expression of LSECtin and PVR were included in the statistical analysis.ResultsHigh positive rates of LSECtin were found in the patients with NSCLC who were nonsmokers, at advanced stages, or had lung adenocarcinoma. Patients with positive LSECtin expression had a significantly lower survival rate (P=0.008) and shorter OS (P=0.017) than those with negative LSECtin. Significant correlation was found between the LSECtin and PVR expression in the patients with NSCLC (P<0.001).ConclusionsThe increased expression of LSECtin was related to the poor prognosis of patients with NSCLC after tumor resection and has the potential value for predicting the prognosis of these patients. The positive correlation between LSECtin and PVR in NSCLC provides a theoretical basis for the future combination therapy of immune checkpoints.

Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution.

Small cell lung cancer (SCLC) has recently been subcategorized into neuroendocrine (NE)‐high and NE‐low subtypes showing ‘immune desert’ and ‘immune oasis’ phenotypes, respectively. Here, we aimed to characterize the tumor microenvironment according to immune checkpoints and NE subtypes in human SCLC tissue samples at the protein level. In this cross‐sectional study, we included 32 primary tumors and matched lymph node (LN) metastases of resected early‐stage, histologically confirmed SCLC patients, which were previously clustered into NE subtypes using NE‐associated key RNA genes. Immunohistochemistry (IHC) was performed on formalin‐fixed paraffin‐embedded TMAs with antibodies against CD45, CD3, CD8, MHCII, TIM3, immune checkpoint poliovirus receptor (PVR), and indoleamine 2,3‐dioxygenase (IDO). The stroma was significantly more infiltrated by immune cells both in primary tumors and in LN metastases compared to tumor nests. Immune cell (CD45+ cell) density was significantly higher in tumor nests (P = 0.019), with increased CD8+ effector T‐cell infiltration (P = 0.003) in NE‐low vs NE‐high tumors. The expression of IDO was confirmed on stromal and endothelial cells and was positively correlated with higher immune cell density both in primary tumors and in LN metastases, regardless of the NE pattern. Expression of IDO and PVR in tumor nests was significantly higher in NE‐low primary tumors (vs NE‐high, P < 0.05). We also found significantly higher MHC II expression by malignant cells in NE‐low (vs NE‐high, P = 0.004) tumors. TIM3 expression was significantly increased in NE‐low (vs NE‐high, P < 0.05) tumors and in LN metastases (vs primary tumors, P < 0.05). To our knowledge, this is the first human study that demonstrates in situ that NE‐low SCLCs are associated with increased immune cell infiltration compared to NE‐high tumors. PVR, IDO, MHCII, and TIM3 are emerging checkpoints in SCLC, with increased expression in the NE‐low subtype, providing key insight for further prospective studies on potential biomarkers and targets for SCLC immunotherapies.

Prognostic significance of tumor poliovirus receptor and CTLA4 expression in patients with surgically resected non-small-cell lung cancer.

Poliovirus receptor (PVR) is a tumor promoter and a regulatory checkpoint that enhances immunosuppression. We investigated PVR expression by applying immunohistochemistry (IHC) staining. A positive association existed between PVR expression and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) expression in patients with surgically resected non-small-cell lung cancer (NSCLC). PVR expression is a prognosis predictor of lung adenocarcinoma. To investigate the prognostic significance of PVR expression and CTLA4 expression for surgically resected NSCLC. The medical records of 108 Chinese patients with primary NSCLC who underwent surgery were retrospectively reviewed. The expression of PVR and CTLA4 were measured through IHC. Clinical characteristics, the association between PVR and CTLA4, and the prognostic significance of PVR were analyzed. A significant positive association was observed between PVR and CTLA4 expression in NSCLC (P = 0.016). PVR had a high positive rate among females, nonsmokers, and patients with adenocarcinoma and advanced lung cancer. The overall survival (OS) of patients with negative PVR expression was significantly longer than that of patients with positive PVR expression (P = 0.049), especially among females (P = 0.03) and nonsmokers (P = 0.025). Multivariate analysis results showed that advanced tumor stage and PVR expression were independent prognosis predictors of poor OS. PVR can potentially serve as a prognostic predictor and biomarker for NSCLC and cancer anti-CTLA4 immunotherapy response.

Bone Marrow Stromal Cell-Derived IL-8 Upregulates PVR Expression on Multiple Myeloma Cells via NF-kB Transcription Factor.

Bone marrow stromal cells (BMSCs) strongly contribute to multiple myeloma (MM) progression, promoting the survival and growth of malignant plasma cells (PCs). However, the possible impact of these cells on the immune-mediated recognition of MM cells remains largely unknown. DNAM-1 activating receptor plays a prominent role in NK cell anti-MM response engaging the ligands poliovirus receptor (PVR) and nectin-2 on malignant PCs. Here, we analysed the role of MM patient-derived BMSCs in the regulation of PVR expression. We found that BMSCs enhance PVR surface expression on MM cells and promote their NK cell-mediated recognition. PVR upregulation occurs at transcriptional level and involves NF-kB transcription factor activation by BMSC-derived soluble factors. Indeed, overexpression of a dominant-negative mutant of IKBα blocked PVR upregulation. IL-8 plays a prominent role in these mechanisms since blockade of CXCR1/2 receptors as well as depletion of the cytokine via RNA interference prevents the enhancement of PVR expression by BMSC-derived conditioned medium. Interestingly, IL-8 is associated with stromal microvesicles which are also required for PVR upregulation via CXCR1/CXCR2 signaling activation. Our findings identify BMSCs as regulators of NK cell anti-MM response and contribute to define novel molecular pathways involved in the regulation of PVR expression in cancer cells.

The interaction of Multiple Sclerosis risk loci with Epstein-Barr virus phenotypes implicates the virus in pathogenesis

Translating the findings of genome wide association studies (GWAS) to new therapies requires identification of the relevant immunological contexts to interrogate for genetic effects. In one of the largest GWAS, more than 200 risk loci have been identified for Multiple Sclerosis (MS) susceptibility. Infection with Epstein-Barr virus (EBV) appears to be necessary for the development of Multiple Sclerosis (MS). Many MS risk loci are associated with altered gene expression in EBV infected B cells (LCLs). We have interrogated this immunological context to identify interaction between MS risk loci and EBV DNA copy number, intrinsic growth rate and EBV encoded miRNA expression. The EBV DNA copy number was associated with significantly more risk alleles for MS than for other diseases or traits. EBV miRNAs BART4-3p and BART3-5p were highly associated with EBV DNA copy number and MS risk loci. The poliovirus receptor (PVR) risk SNP was associated with EBV DNA copy number, PVR and miRNA expression. Targeting EBV miRNAs BART4-3p and BART3-5p, and the gene PVR, may provide therapeutic benefit in MS. This study also indicates how immunological context and risk loci interactions can be exploited to validate and develop novel therapeutic approaches.

Targeting the TIGIT-PVR immune checkpoint axis as novel therapeutic option in breast cancer

ABSTRACTImmune checkpoints are intensively investigated as targets in cancer therapy. T-cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) and its ligand poliovirus receptor (PVR) are recently emerging as novel promising targets in immunotherapy. Here, we show that high expression of PVR represents an independent prognostic marker being associated with poor outcome for breast cancer patients. Furthermore, PVR mRNA, as well as protein expression, is associated with more aggressive breast cancer subtypes such as HER2 positive and triple-negative breast cancer. In vitro, blocking TIGIT or PVR resulted in enhanced immune cell-mediated lysis of breast cancer cell lines SKBR-3, MDA-MB-231, MDA-MB-468, and BT549 and additionally increased the cytotoxic effects of a bispecific T cell engager BiTE® antibody construct targeting EGFR. Taken together, our data identify the immune checkpoint factor PVR as a novel prognostic marker in breast cancer and indicate that blocking the TIGIT-PVR axis might represent a novel therapeutic option for the treatment of breast cancer patients.

Oncolytic Activity of the Vaccine Strain of Type 3 Poliovirus on the Model of Rat Glioma C6 Cells.

Rat glioma cell line C6 expressing human poliovirus receptor (PVR) and susceptible to polioviruses (C6-PVR-BFP) was used to produce a clone with knockout of IFNα/β (Ifnar1) receptor subunit 1 gene (Ifnar1). The sensitivity of C6-PVR-BFP cells to the vaccine strain of poliovirus type 3 (PV3) depended on the signaling pathways of the cell response to type 1 IFN. Using the model of subcutaneous tumor xenografts, we demonstrated oncolytic activity of PV3 against C6-PVR-BFP cells that depended on the expression of PVR and increased considerably upon disturbances in IFN response pathways.