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Background: Testicular germ cell tumor (TGCT) is a type of tumor with relatively lower incidence but being more prevalent in young men. The expression of programmed cell death ligand 1 (PD-L1) serves as a potential biomarker for predicting the survival outcomes of other tumors. Some studies discovered higher prevalence of PD-L1 in TGCT patients who achieved favorable treatment outcomes, while other studies showed lower or absent expression of PD-L1 in TGCT with the better prognosis as well. Therefore, in order to address this controversy and clarify the association between the expression of PD-L1 and pathological features and prognosis of TGCT, this meta-analysis was conducted. Methods: A comprehensive literature search was performed using following search terms: "testis", "testicle", "testicular", "cancer", "carcinoma", "tumor", "neoplasm", "programmed cell death ligand 1", "programmed death ligand 1", "PD-L1", "PDL1", "B7 homolog 1", "B7-H1", "B7H1" and "CD274". Relevant studies were retrieved according to the inclusion criteria from reputable databases including PubMed, Embase, Web of Science, Cochrane Library and China National Knowledge Infrastructure (CNKI). These studies investigated the expression of PD-L1 in both tumor cells and tumor infiltrating immune cells (TIICs) in TGCT. The overall proportion of PD-L1 positivity was assessed using R programming. Pooled hazard ratio (HR) and odds ratio (OR) with corresponding 95% confidence interval (CI) were calculated using Revman software to evaluate the involvement of PD-L1 expression in TGCT. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality assessment of included studies. Sensitivity analysis and publication bias evaluation were subsequently performed. Results: A total of eight eligible studies compromising 1,589 patients diagnosed with TGCT were finally included in this study. PD-L1 positivity was detected in 31% and 41% of TGCT patients' tumor cells and TIICs, respectively. The pooled data demonstrated a significant association between elevated PD-L1 expression levels in TIICs and a favorable prognosis characterized by the reduced disease progression and relapse events (HR =0.21, 95% CI: 0.13-0.33). Furthermore, PD-L1+ TIICs exhibited higher prevalence rates in seminoma (OR =2.11, 95% CI: 1.57-2.84) and embryonal carcinoma (OR =6.23, 95% CI: 2.42-16.02) patients. Notably, PD-L1 expression in TIICs displayed a tendency to increase in TGCT patients with lower stages or without lymph node metastasis. Conclusions: PD-L1 expression was observed in choriocarcinoma tumor cells, while yolk sac tumor and teratoma tumor cells exhibited lower or absent expression of PD-L1. Conversely, PD-L1 expression in TIICs was associated with seminoma and embryonal carcinoma, which was more commonly observed in TGCT patients with lower stages and better prognosis, thereby providing a theoretical foundation for the application of immunotherapy in relapsed/refractory TGCT patients.

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Clinical evidences of neoadjuvant immunotherapy in patients with mismatch repair deficient/microsatellite instability-high status (dMMR/MSI-H) colorectal cancer have not been well received. A 36-year-old man complained of recurrent right upper quadrant pain for more than 1 year, and the symptoms were not significantly relieved after 10 days of oral Changyanning tablet. The patient was finally diagnosed as dMMR/MSI-H colon cancer. Tumor regression was achieved after seven cycles of envafolimab treatment, and the patient obtained postoperative pathological complete response (pCR). Here, we report a case of MSI-H/dMMR transverse colon cancer, who obtained pCR after neoadjuvant envafolimab (a novel subcutaneous single-domain anti-PD-L1 antibody) with a favorable safety profile, aiming to enhance the experiences of comprehensive diagnosis and treatment of colon cancer.

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Immune checkpoint inhibitors (ICIs) are a type of immunotherapy which can be used in the treatment of colorectal cancer. The authors here report the functions of envafolimab (a type of ICI) used before surgery to shrink tumor volume in colorectal cancer. A 36-year-old man suffered from repeated illness of right upper quadrant for over 1 year, and the illness were not recovered after 10 days of oral Changyanning tablet. The patient was finally diagnosed with colorectal cancer. After seven cycles of envafolimab treatment, tumor volume was significantly decreased, and the patient obtained favorable surgical outcomes with tolerable safety after surgery.

Asunto(s)

Neoplasias del Colon , Inestabilidad de Microsatélites , Terapia Neoadyuvante , Humanos , Masculino , Adulto , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/terapia , Reparación de la Incompatibilidad de ADN , Inhibidores de Puntos de Control Inmunológico/uso terapéutico

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BACKGROUND: Inhibitors of programmed cell death ligand 1 (PD-L1) and vascular endothelial growth factor receptor 2 (VEGFR2) are commonly used in the clinic, but they are beneficial for only a minority of glioblastoma multiforme (GBM) patients. GBM has significant immunosuppressive properties, and there are many immunosuppressive cells and dysfunctional effector T-cell in the tumor microenvironment (TME), which is one of the important reasons for the failure of clinical treatment of GBM. P21-activated kinase 4 (PAK4) is a threonine protein kinase, and as a pivotal immune suppressor in the TME. PAK4 knockdown attenuates vascular abnormalities and promotes T-cell infiltration. METHODS: Using RNA sequencing (RNA-seq) technology, western blotting, and immunofluorescence, we identified changes in genes expression following VEGFR2 knockdown. The impact of anti-PD-L1 and anti-VEGFR2 on GBM cells apoptosis was assessed using coculture assays, western blotting, and flow cytometry. Additionally, the therapeutic efficacy of anti-PD-L1 and anti-VEGFR2 therapy was evaluated through in vivo experiments, immunohistochemistry, and immunofluorescence. RESULTS: Our studies revealed that VEGFR2 binds and phosphorylates signal transducer and activator of transcription 3 (p-STAT3), thereby regulating the expression of PAK4. Anti-PD-L1 and anti-VEGFR2 therapy can increase the secretion of interferon-gamma (IFN-γ), granzyme B, and perforin by immune cells and promoting the cytotoxic effects of cytotoxic cluster of differentiation 8 (CD8)+ T cells, and overexpression of PAK4 could reverse this effect. We also demonstrated that combination therapy with anti-PD-L1 and anti-VEGFR2 agents prevents tumor growth in an intracranial tumor model. CONCLUSIONS: Our results support that anti-VEGFR2 therapy can downregulate PAK4, reprogram the TME by increasing CD8+ T cells infiltration and activation, and enhance the therapeutic effect of anti-PD-L1 therapy on GBM cells.

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Antígeno B7-H1 , Glioblastoma , Microambiente Tumoral , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Humanos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Antígeno B7-H1/metabolismo , Ratones , Animales , Línea Celular Tumoral

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Background: Programmed cell death ligand 1 (PD-L1) expression in non-small cell lung carcinoma (NSCLC) is a crucial factor in predicting responses to immunotherapy. This systematic review and meta-analysis focuses on the prevalence of PD-L1 expression and clinicopathological features among Hispanic/Latino (H/L) populations. Methods: Embase, LILACS, Medline, and Virtual Health Library were searched for studies that evaluated the prevalence of PD-L1 in H/L patients. The protocol was submitted to PROSPERO with ID CRD42023488547. We employed the Joanna Briggs Institute Checklist for Systematic Reviews and Research Syntheses to assess the methodological quality and applicability of the included studies. Meta-analyses were done to determine the prevalence using a random effects model. Results: The meta-analysis, encompassing 21 articles with 16,486, revealed that 80.2% of patients had PD-L1 expression data available (n=13,222). The prevalence calculated of PD-L1 expression in Latino NSCLC patients was 55% [95% confidence interval (CI): 0.54-0.55], with 31% (95% CI: 0.27-0.36) showing a tumoral proportion score (TPS) of 1-49%, and 23% (95% CI: 0.16-0.30) registering a TPS ≥50%. Higher expression was observed in male gender, smoking, adenocarcinoma subtypes, poor tumor differentiation, and advanced stages. PD-L1 expression was most frequent in EGFR wild-type status (82.5%) with a odds ratio (OR) 1.54 (95% CI: 1.24-1.92) and PD-L1 expression was associated with ALK positive (OR =1.54; 95% CI: 1.24-1.92). Conclusions: This meta-analysis provides a comprehensive overview of PD-L1 expression in NSCLC in the H/L population. The findings underscore the significant prevalence of PD-L1 expression and emphasize the relevance of immunotherapy in this population. Understanding the clinicopathological features associated with PD-L1 expression can contribute to tailored treatment strategies for NSCLC in Latin America.

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BACKGROUND: Primary extragonadal choriocarcinoma (PEGCC) in male is rare. It is highly malignant, typically presents with distant metastasis at the time of diagnosis, and responds poorly to treatment. Because of its associated high levels of PD-L1, the PD-1/PD-L1 pathway is a likely therapeutic target. Herein, we report our experience of treating pediatric PEGCC in six boys at a tertiary hospital. METHODS: We analyzed the data of six boys with pathologically confirmed PEGCC between 2009 and 2021. Their clinicodemographic and histopathological characteristics as well as treatments and clinical outcomes were retrieved from their medical charts. RESULTS: The patients' median age was 15 (range: 12-17) years. The most common primary tumor site was the mediastinum (67%, 4/6), with one case each in the retroperitoneum (16.7%) and brain (16.7%). Except for the patient with brain PEGCC, all presented with metastasis at the time of diagnosis. The following metastatic sites were observed: the lungs (100%, 5/5), brain (3/5, 60%), liver (3/5, 60%), kidneys (2/5, 40%), and spleen (1/5, 20%). Most patients had dry cough, dyspnea, and hemoptysis at initial presentation, likely due to lung metastasis. Serum human chorionic gonadotropin (HCG) levels were highly elevated in all patients. All patients received platinum-based cytotoxic chemotherapy. The patient with brain choriocarcinoma underwent surgical tumor resection; all others underwent only surgical biopsy. Strong positive PD-L1 immunohistochemical staining was noted for two patients. One patient received the PD-L1 inhibitor pembrolizumab and achieved a good response. Our cohort's 1-year survival rate was 33.3%, with a median survival of 4.34 months. Serum HCG levels remained normal in the two survivors during follow-up visits. CONCLUSION: The poor response to current platinum-based chemotherapy remains a major challenge in the management of pediatric PEGCC. Adding pembrolizumab to a conventional chemotherapy regimen may improve the outcomes in boys with PEGCC.

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Background: Immunochemotherapy was an emerging neoadjuvant treatment mode that can potentially benefit patients with esophageal carcinoma, but its synergistic mechanism and impact on the tumor immune microenvironment were still unclear. The purpose of this study was to investigate the outcomes of neoadjuvant chemotherapy (nCT) and neoadjuvant immunochemotherapy (nICT) in tumor microenvironment (TME) remodeling among patients with esophageal squamous cell carcinoma (ESCC) and to evaluate the prognostic value of immune-related biomarkers and clinicopathological characteristics. Methods: Patients with locally advanced ESCC who underwent neoadjuvant therapy followed by esophagectomy at the Fourth Hospital of Hebei Medical University between December 2019 and March 2022 were enrolled in this retrospective study. We examined TME features and immune antigen-related biomarkers before and after neoadjuvant therapy. Logistic and Cox regression model were used to evaluate the correlation between these factors and other clinical features and outcomes. Results: A total of 50 eligible participants were analyzed, including 31 males (62%), 25 patients of ≥65 years old, 4/28/18 of upper/middle/lower thoracic cancer, 25/17/8 of poor/moderate/high tumor differentiation, 8/42 of cT1+2/T3+4 stages and 30/20 of cN0/N+ stages. In the entire cohort, the rates of pathological complete response (pCR) and major pathological response (MPR) were 18% and 30%, respectively. pCR rates were 7.1% and 22.2% (χ2=0.699; P=0.40) MPR rates were 7.1% and 38.9% (χ2=4.837; P=0.03) in the nCT and nICT groups, respectively. Compared with the non-pCR patients, the pCR patients had a higher baseline programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) positive expression rate (16.7% vs. 77.8%, χ2=13.089; P<0.001). Following neoadjuvant therapy, the expression rates of PD-L1, CD3+ T cells, and CD8+ T cells in the tumor tissue was higher in the nICT group compared to the nCT group (P<0.05). Deficient expression of mismatch repair (MMR) genes was only observed in one patient (2%). Among patient-related biomarkers, lymphocyte and neutrophil counts decreased after treatment, with no significant changes in the neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio (PLR). Cox regression analysis showed that pretreatment, well-differentiated tumors and positive PD-L1 status were positive predictors of MPR (P<0.05). MPR was an independent predictor of disease-free survival (DFS) (P=0.03). Conclusions: Compared to nCT, nICT could more significantly upregulates PD-L1 TPS, PD-L1 combined positive score (CPS), CD3+ T cells, and CD8+ T cells. Pretreatment tumor differentiation and PD-L1 TPS level could be predictive of MPR. Our findings suggested that the combination of chemotherapy and immunotherapy may be more beneficial for activating anti-tumor immunity in the TME.

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Background: The tumor microenvironment (TME) plays an important role in tumor progression and immunotherapy responses in non-small cell lung cancer (NSCLC). The programmed cell death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) checkpoint is a central mediator of immunosuppression in the TME. However, there is still a need to identify additional biomarkers that could reflect the difference in TME and PD-L1 expression in NSCLC patients. To this end, we focused on the expression of G-protein-coupled receptor family C group 5 type A (GPRC5A) in NSCLC. GPRC5A, is a retinoic acid-inducible gene that plays multiple roles in NSCLC. However, little is known about the role of GPRC5A in regulating the TME and PD-L1. Our objective was to describe the critical role of GPRC5A expression in NSCLC in the setting of immune cell infiltration. Methods: We identified the relationship between GPRC5A expression and the clinicopathologic characteristics of NSCLC patients in the Fudan University Shanghai Cancer Center (FUSCC) cohort. Furthermore, we validated GPRC5A as a predictive biomarker by using public databases to reveal the relationship between GPRC5A expression and immune cell infiltration. To correlate the expression of GPRC5A with the spatial distribution of PD-L1 in NSCLC samples, we performed multiplex immunohistochemistry (mIHC). Results: Low GPRC5A expression is associated with earlier pathological stage (pStage). Analysis of immune cell infiltration indicates there is a relationship between low GPRC5A expression and increased infiltration of CD8+ T cells, activated CD4+ T cells, and M1 macrophages within the TME. Furthermore, low GPRC5A expression is associated with an increased immunophenotype score (IPS) in NSCLC. Additionally, analysis of mIHC reveals there is a correlation between low GPRC5A expression and spatial distribution of tumoral PD-L1 expression. Conclusions: Our study revealed the relationship between low expression of GPRC5A and earlier pStage in NSCLC. Furthermore, we observed that low expression of GPRC5A is associated with increased infiltration of immune cells, higher IPS, and spatial distribution of PD-L1-positive tumor cells. Therefore, we speculate that low expression of GPRC5A is associated with immunotherapy, but further validation is still required.

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The impact of gut and oral microbiota on the clinical outcomes of patients with oral squamous cell carcinoma (OSCC) is unknown. We compared the bacterial composition of dental plaque and feces between patients with OSCC and healthy controls (HCs). Fecal and dental plaque samples were collected from 7 HCs and 18 patients with OSCC before treatment initiation. Terminal restriction fragment-length polymorphism analysis of 16S rRNA genes was performed. Differences in bacterial diversity between the HC and OSCC groups were examined. We compared the occupancy of each bacterial species in samples taken from patients with OSCC and HCs and analyzed the correlation between PD-L1 expression in the tumor specimens and the occupancy of each bacterial species. The gut and oral microbiota of patients with OSCC were more varied than those of HCs. Porphyromonas and Prevotella were significantly more abundant in patients with OSCC than in HCs. The abundance of Clostridium subcluster XIVa in the gut microbiota of the PD-L1-positive group was significantly greater than that in the PD-L1-negative group. The oral and gut microbiomes of patients with OSCC were in a state of dysbiosis. Our results suggest the possibility of new cancer therapies targeting these disease-specific microbiomes using probiotics and synbiotics.

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Carcinoma de Células Escamosas , Microbioma Gastrointestinal , Neoplasias de la Boca , ARN Ribosómico 16S , Humanos , Microbioma Gastrointestinal/genética , Neoplasias de la Boca/microbiología , Masculino , Femenino , Persona de Mediana Edad , Carcinoma de Células Escamosas/microbiología , ARN Ribosómico 16S/genética , Anciano , Heces/microbiología , Boca/microbiología , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Microbiota/genética , Adulto , Disbiosis/microbiología , Placa Dental/microbiología , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Estudios de Casos y Controles

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Background: The efficacy of immunotherapy for brain metastases from small cell lung cancer (SCLC) is relatively low, and the tumor microenvironment of SCLC brain metastases is still unknown. Therefore, we investigated the distribution of tumor-infiltrating lymphocytes (TILs) and the expression of programmed cell death-ligand 1 (PD-L1) in patients with brain metastases from SCLC to explore the tumor microenvironment of SCLC brain metastases. Methods: A retrospective analysis was performed on 12 surgical specimens of brain metastases from patients with SCLC treated in the Department of Neurosurgery of The First Affiliated Hospital of Anhui Medical University from June 2017 to June 2022. The inclusion criteria for this study were the following: (I) a pathologically confirmed diagnosis of SCLC brain metastases; (II) surgical resection of brain metastases; (III) age >18 years; (IV) and complete clinical data. Patient-related data were retrieved from the inpatient medical record system, telephone follow-up of patients date of death, and overall survival (OS). The immunofluorescence-based tissue microenvironment analysis panel (MAP) was utilized for the detection of TILs, including CD3, CD8, programmed cell death 1 (PD-1), and PD-L1, in formalin-fixed and paraffin-embedded archival specimens of brain metastases. The expression levels of PD-L1 in tumor cells were detected by immunohistochemistry. The correlation between the OS and the above-mentioned markers was analyzed in the 12 patients. Results: Twelve patients were included in the study. The patients' ages ranged from 51-78 years with a median of 68 years, with 1 female and 11 males. Among 12 patients with SCLC brain metastases: positive rates of CD3+ TILs in the tumor parenchyma vs. tumor stroma were 0.60%±0.94% vs. 1.76%±2.72% (P=0.01), respectively; positive rates of CD8+ TILs in the tumor parenchyma vs. tumor stroma were 0.80%±0.78% vs. 2.46%±3.72% (P=0.02), respectively. There was no co-expression of CD8+ and PD-1+ TILs in the tumor parenchyma of 11 cases, and the infiltration density of coexpressed CD3+ and PD-1+ TILs was more than 10/mm2 in only 1 case. There was no coexpression of CD3+ and PD-1+ TIL in the stroma of 10 cases, and the infiltration density of CD8+ and PD-1+ TILs was more than 10/mm2 in 2 cases. Immunohistochemistry was used to detect the expression of PD-L1 in 12 cases of SCLC metastatic lesions, and 3 cases (25%) were positive. Survival analysis showed that patients with positive intraepithelial CD3+ TILs had significantly longer OS [hazard ratio 3.383, 95% confidence interval (CI): 0.959-11.940; P=0.04]. Conclusions: Our study further demonstrated the immune microenvironment of SCLC brain metastases. The distribution of TILs in SCLC brain metastases is low and mainly distributed in the stroma, with the expression of PD-L1 in these tumor tissues being low. Further exploration of the immune microenvironment of SCLC brain metastases is of great significance for potential treatment.

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Background: The programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is a potent negative regulator of T-cell-mediated immune response that is upregulated in many neoplasms. Pancreaticobiliary adenosquamous carcinoma (PB-ASC) is an aggressive cancer that carries a poorer prognosis compared with pure pancreaticobiliary adenocarcinoma (PB-AC). To date, there is little published information regarding PD-L1 expression in PB-ASC. The aim of the study was to examine the relationship between PD-L1 expression and tumor-infiltrating lymphocytes in PB-ASC and PB-AC. Methods: We evaluated 15 PB-ASCs (10 pancreatic, 5 gallbladder) and 34 control PB-ACs (22 pancreatic ductal, and 12 gallbladder) for tumor expression of PD-L1 using anti-PD-L1 (E1L3N) antibody. All tumors were classified into three immune phenotypes: immune inflamed (II), immune excluded (IE), and immune desert (ID) according to the distribution of tumor-infiltrating lymphocytes in tumor tissues. Results: The frequency of PD-L1 expression was significantly higher in PB-ASC (10/15; 66.7%) than in PB-AC (3/34; 8.8%). In PB-ASC, PD-L1 expression occurred exclusively in the squamous component in six cases, exclusively in the glandular component in one case, and in both the squamous and the glandular components in three cases. PD-L1 expression in PB-ASC was irrespective of the tumor immune status, whereas its expression in PB-AC was observed only in tumors with the II or IE phenotype. The ID phenotype was relatively rare (4/15; 26.7%) in PB-ASC compared with PB-AC (22/34; 65%; P=0.02). Conclusions: PB-ASCs are notably enriched in inflammatory response and showed significantly higher PD-L1 expression than PB-AC (P<0.001), suggesting a potential therapeutic role for immune checkpoint inhibitors in managing patients with PB-ASC.

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BACKGROUND: Primary cardiac angiosarcoma(PCA) has a low incidence rate and poor prognosis. Currently, no unified clinical treatment standards are available. CASE PRESENTATION: We report the case of a 48-year-old man presenting chest tightness, breathlessness, and dyspnea. Imaging and postoperative histopathologic studies confirmed PCA and that the tumor had invaded the entire right atrium. The patient developed progressive disease (PD) during postoperative radiotherapy. We used immunotherapy combined with targeted therapy based on the results of molecular profile and evaluation of tertiary lymphoid structures (TLSs) and programmed cell death-ligand 1 (PD-L1). After treatment, the metastatic lymph nodes of the patient were reduced to a certain extent, indicating that combination therapy was effective. CONCLUSION: To the best of our knowledge, this is the first report of radiotherapy combined with anti-PD-1 and tyrosine kinase inhibitors(TKI) for PCA. In addition, this is the first report on immunotherapy for PCA based on new evaluation methods, including TLSs, PD-L1, and genomic profile.

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Hemangiosarcoma , Neoplasias Pulmonares , Estructuras Linfoides Terciarias , Masculino , Humanos , Persona de Mediana Edad , Antígeno B7-H1 , Hemangiosarcoma/diagnóstico , Hemangiosarcoma/terapia , Neoplasias Pulmonares/patología

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Background: Immunotherapies using anti-programmed cell death ligand-1 (PD-L1) agents have recently shown remarkable outcomes in patients with non-small cell lung cancer (NSCLC). However, there was a poor correlation between PD-L1 expression and treatment response. Many researchers have focused on the clinicopathological factors associated with prognosis, but the results are conflicting. In the present study, we investigated the clinicopathological significance of PD-L1 overexpression in NSCLC cells. Methods: In total, 344 NSCLC cases with PD-L1 assays were retrospectively analyzed. PD-L1 expression was evaluated via immunohistochemical staining using antibodies against SP263 and SP142. The correlation between clinicopathological factors and PD-L1 expression was analyzed for various clinicopathological features. Results: PD-L1 expression significantly correlated with several poor clinicopathological factors, including the solid component of adenocarcinoma, lymphatic invasion, and recurrence. Squamous cell carcinoma, older age, and male sex were also associated with PD-L1 expression. However, we could not observe correlation between PD-L1 expression and disease-free survival (DFS). A novel finding was that lower metastasis was associated with high PD-L1 expression of SP142 in tumor-infiltrating immune cells (ICs). Conclusions: PD-L1 expression in NSCLC is associated with adverse clinicopathological features and recurrence; therefore, it could be utilized to predict poor prognosis. Furthermore, the high PD-L1 expression of SP142 in tumor-infiltrating ICs could be a potential marker for low metastasis.

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Programmed cell death protein-1 (PD-1) is an immune checkpoint protein, PD-1 interaction with PD ligand-1 (PD-L1) is essential for maintaining immunological tolerance. The study aimed to study and compare the levels of PD-1 and PD-L1 in lesional and nonlesional skin of lichen planus (LP) patients and compare these levels to normal healthy controls to assess their role in the pathogenesis of LP. This case-control study involved 30 patients with LP and 30 healthy age-and sex-matched controls. After clinical assessment of the severity by LP severity index score (LPSI), skin biopsies were taken from lesional and nonlesional skin of LP patients and from normal skin in healthy controls for assessment of the tissue levels of PD-1 and PD-L1 by ELISA. The tissue levels of both PD-1 and PD-L1 were significantly higher in healthy controls than in both lesional and nonlesional skin of LP patients (P < 0.001). Also, significantly higher PD-l and PD-L1 levels in nonlesional skin than in lesional skin of LP patients were reported (P < 0.001). No significant correlations were found between lesional and nonlesional PD-1, PD-L1 levels, or LPSI score. Based on the fact that PD-1/PD-L1 interaction is important to maintain tolerance and protection against autoimmune diseases, in addition to our study results that revealed lower levels of PD-1/PD-L1 in LP skin than in healthy skin, we can conclude that PD-1/PDL-1 may be incriminated in the pathogenesis of LP. ClinicalTrials.govID: NCT04892381.

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Antígeno B7-H1 , Liquen Plano , Humanos , Antígeno B7-H1/metabolismo , Estudios de Casos y Controles , Liquen Plano/metabolismo , Ligandos , Receptor de Muerte Celular Programada 1

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Gastric cancer is a leading global cause of cancer-related mortality. In the past, survival achieved in metastatic disease with chemotherapy was less than 1 year. The advent of immune checkpoint inhibitors has changed the treatment of gastric cancer. With demonstration of single agent activity for anti-programmed cell death protein 1 (anti-PD-1) agents in gastric cancer with a particularly high degree of activity in microsatellite instability (MSI) high cancers, global clinical trials added nivolumab and pembrolizumab to first line chemotherapy. Improvements in progression free survival, overall survival and increased response rates led to regulatory approval of these agents in the U.S. The benefit in survival seems limited, however, to patients with programmed cell death ligand 1 (PD-L1) positive or MSI high cancers. Adjuvant therapy with nivolumab improved disease-free survival after chemoradiotherapy and surgery in esophageal and gastroesophageal junction adenocarcinoma in patients with residual disease resected at surgery, and is a new care standard. Results of ongoing trials adding immune checkpoint inhibitors to perioperative chemotherapy in gastric cancer are anxiously awaited. In locally advanced MSI high gastric cancer, immune checkpoint inhibitor therapy is being explored as preoperative therapy given the demonstration of a high degree of pathologic complete response to these agents. Some trials may offer patients nonoperative management if a complete response is achieved.

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Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Estados Unidos , Neoplasias Gástricas/patología , Nivolumab/farmacología , Nivolumab/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Esofágicas/patología , Terapia Combinada , Antígeno B7-H1/metabolismo , Antígeno B7-H1/uso terapéutico

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Chemotherapy and immunotherapy are two important modalities in cancer management. However, due to multiple reasons, a monotherapy is only partially effective. Hence, if used concurrently in targeted and stimuli-responsive manner, it could have been superior therapeutically. To facilitate co-delivery of chemotherapeutic and immunotherapeutic agent to the target cancer cells, engineered nanoparticles, i.e., a pH-responsive polymer PLGA-coated magnetic silica nanoparticles (Fe3O4-SiO2-PLGA-PDA-PTX-siRNA NPs) encapsulating paclitaxel (PTX) and siRNA against programmed cell death ligand-1 (PD-L1) are synthesized and characterized. Developed nanoparticles demonstrated pH-sensitive sustained drug release up to 10 days. In vitro 4T1 cell line studies showed efficient cellular uptake, PD-L1 gene downregulation, and apoptosis. Further, in vivo efficacy studies carried out in the mice model demonstrated a significant reduction of tumor growth following treatment with dual-Fe3O4-SiO2-PLGA-PDA-PTX-siRNA NPs as compared with monotherapy with Fe3O4-SiO2-PLGA-PDA-PTX NPs. The high therapeutic efficacy observed with dual-Fe3O4-SiO2-PLGA-PDA-PTX-siRNA NPs was mainly due to the cytotoxic effect of PTX combined with targeted silencing of the gene of interest, i.e., PD-L1, which in turn improve CD8+ T cell-mediated cancer cell death as evident with increased proliferation of CD8+ T cells in co-culture experiments. Thereby, dual-Fe3O4-SiO2-PLGA-PDA-PTX-siRNA NPs may have a promising anti-cancer treatment potential against breast cancer; however, the beneficial effects of dual loading of PTX + PD-L1 siRNA may be corroborated against other cancer models such as lung and colorectal cancer models as well as in clinical trials.

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Antígeno B7-H1 , Inmunoterapia , Ratones Endogámicos BALB C , Paclitaxel , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , ARN Interferente Pequeño , Dióxido de Silicio , Animales , Dióxido de Silicio/química , Dióxido de Silicio/administración & dosificación , Paclitaxel/administración & dosificación , Paclitaxel/química , Paclitaxel/farmacología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Línea Celular Tumoral , Inmunoterapia/métodos , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/química , Femenino , Ratones , Liberación de Fármacos , Nanopartículas de Magnetita/química , Apoptosis/efectos de los fármacos , Nanopartículas/química , Nanopartículas/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/química , Concentración de Iones de Hidrógeno , Humanos , Portadores de Fármacos/química

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Immunotherapy targeting PD-L1 is still ineffective for a wide variety of tumors with high unpredictability. Deploying combined immunotherapy with alternative targeting is practical to overcome this therapeutic resistance. Here, the deficiency of serine-threonine kinase STK24 is observed in tumor cells causing substantial attenuation of tumor growth in murine syngeneic models, a process relying on cytotoxic CD8+ T and NK cells. Mechanistically, STK24 in tumor cells associates with and directly phosphorylates AKT at Thr21, which promotes AKT activation and subsequent PD-L1 induction. Deletion or inhibition of STK24, by contrast, blocks IFN-γ-mediated PD-L1 expression. Various murine models indicate that in vivo silencing of STK24 can significantly enhance the efficacy of the anti-PD-1 blockade strategy. Elevated STK24 levels are observed in patient specimens in multiple tumor types and inversely correlated with intratumoral infiltration of cytotoxic CD8+ T cells and with patient survival. The study collectively identifies STK24 as a critical modulator of antitumor immunity, which engages in AKT and PD-L1/PD-1 signaling and is a promising target for combined immunotherapy.

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Antígeno B7-H1 , Linfocitos T CD8-positivos , Humanos , Animales , Ratones , Antígeno B7-H1/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Escape del Tumor , Línea Celular Tumoral

RESUMEN

Evidence recently showed that pleiotropic cytokine interferon-gamma (IFN-γ) in the tumor microenvironment (TME) plays a positive role in hepatocellular carcinoma (HCC) progression through the regulation of liver cancer stem cells (LCSCs) in HCC. The present study explored the role and potential mechanism of mitochondrial programmed cell death-ligand 1 (PD-L1) and its regulation of ferroptosis in modulating the cancer stemness of LCSCs. It was shown that mimicking TME IFN-γ exposure increased the LCSCs ratio and cancer stemness phenotypes in HCC cells. IFN-γ exposure inhibited sorafenib (Sora)-induced ferroptosis by enhancing glutathione peroxidase 4 (GPX4) expression as well reactive oxygen species (ROS) and lipid peroxidation (LPO) generation in LCSCs. Furthermore, IFN-γ exposure upregulated PD-L1 expression and its mitochondrial translocation, inducing dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and correlating with glycolytic metabolism reprogramming in LCSCs. The genetic intervention of PD-L1 promoted ferroptosis-dependent anti-tumor effects of Sora, reduced glycolytic metabolism reprogramming, and inhibited cancer stemness of HCC in vitro and in vivo. Our results revealed a novel mechanism that IFN-γ exposure-induced mitochondrial translocation of PD-L1 enhanced glycolytic reprogramming to mediate the GPX4-dependent ferroptosis resistance and cancer stemness in LCSCs. This study provided new insights into the role of mitochondrial PD-L1-Drp1-GPX4 signal axis in regulating IFN-γ exposure-associated cancer stemness in LCSCs and verified that PD-L1-targeted intervention in combination with Sora might achieve promising synergistic anti-HCC effects.

Asunto(s)

Carcinoma Hepatocelular , Ferroptosis , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Sorafenib/farmacología , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Interferón gamma/genética , Interferón gamma/metabolismo , Ferroptosis/genética , Línea Celular Tumoral , Microambiente Tumoral

RESUMEN

PURPOSE: Due to tumor heterogeneity, immunohistochemistry (IHC) showed poor accuracy in detecting the expression of programmed cell death ligand-1 (PD-L1) in patients. Positron emission tomography (PET) imaging is considered as a non-invasive technique to detect PD-L1 expression at the molecular level visually, real-timely and quantitatively. This study aimed to develop novel peptide-based radiotracers [68Ga]/[18F]AlF-NOTA-IMB for accurately detecting the PD-L1 expression and guiding the cancer immunotherapy. METHODS: NOTA-IMB was prepared by connecting 2,2'-(7-(2-((2,5-dioxopyrrolidin-1-yl)oxy)- 2-oxoethyl)-1,4,7-triazonane-1,4-diyl) diacetic acid (NOTA-NHS) with PD-L1-targeted peptide IMB, and further radiolabeled with 68Ga or 18F-AlF. In vitro binding assay was conducted to confirm the ability of [68Ga]/[18F]AlF-NOTA-IMB to detect the expression of PD-L1. In vivo PET imaging of [68Ga]NOTA-IMB and [18F]AlF-NOTA-IMB in different tumor-bearing mice was performed, and dynamic changes of PD-L1 expression level induced by immunotherapy were monitored. Radioautography, western blotting, immunofluorescence staining and biodistribution analysis were carried out to further evaluate the specificity of radiotracers and efficacy of PD-L1 antibody immunotherapy. RESULTS: [68Ga]NOTA-IMB and [18F]AlF-NOTA-IMB were both successfully prepared with high radiochemical yield (> 95% and > 60%, n = 5) and radiochemical purity (> 95% and > 98%, n = 5). Both tracers showed high affinity to human and murine PD-L1 with the dissociation constant (Kd) of 1.00 ± 0.16/1.09 ± 0.21 nM (A375-hPD-L1, n = 3) and 1.56 ± 0.58/1.21 ± 0.39 nM (MC38, n = 3), respectively. In vitro cell uptake assay revealed that both tracers can specifically bind to PD-L1 positive cancer cells A375-hPD-L1 and MC38 (5.45 ± 0.33/3.65 ± 0.15%AD and 5.87 ± 0.27/2.78 ± 0.08%AD at 120 min, n = 3). In vivo PET imaging and biodistribution analysis showed that the tracer [68Ga]NOTA-IMB and [18F]AlF-NOTA-IMB had high accumulation in A375-hPD-L1 and MC38 tumors, but low uptake in A375 tumor. Treatment of Atezolizumab induced dynamic changes of PD-L1 expression in MC38 tumor-bearing mice, and the tumor uptake of [68Ga]NOTA-IMB decreased from 3.30 ± 0.29%ID/mL to 1.58 ± 0.29%ID/mL (n = 3, P = 0.026) after five treatments. Similarly, the tumor uptake of [18F]AlF-NOTA-IMB decreased from 3.27 ± 0.63%ID/mL to 0.89 ± 0.18%ID/mL (n = 3, P = 0.0004) after five treatments. However, no significant difference was observed in the tumor uptake before and after PBS treatment. Biodistribution, radioautography, western blotting and immunofluorescence staining analysis further demonstrated that the expression level of PD-L1 in tumor-bearing mice treated with Atezolizumab significantly reduced about 3 times and correlated well with the PET imaging results. CONCLUSION: [68Ga]NOTA-IMB and [18F]AlF-NOTA-IMB were successfully prepared for PET imaging the PD-L1 expression noninvasively and quantitatively. Dynamic changes of PD-L1 expression caused by immunotherapy can be sensitively detected by both tracers. Hence, the peptide-based radiotracers [68Ga]NOTA-IMB and [18F]AlF-NOTA-IMB can be applied for accurately detecting the PD-L1 expression in different tumors and monitoring the efficacy of immunotherapy.

Asunto(s)

Antígeno B7-H1 , Neoplasias , Humanos , Ratones , Animales , Antígeno B7-H1/metabolismo , Distribución Tisular , Radioisótopos de Galio/química , Línea Celular Tumoral , Tomografía de Emisión de Positrones/métodos , Péptidos/metabolismo , Inmunoterapia , Neoplasias/diagnóstico por imagen , Neoplasias/terapia

RESUMEN

@#Objective To construct a yeast two-hybrid recombinant bait plasmid of human programmed cell death ligand 1(PD-L1)immunoglobulin variable region(IgV)domain gene,detect its expression in yeast and detect the cytotoxicity and self-activation of PD-L1 IgV protein as well as the interaction between PD-L1 IgV and human thioredoxin(hTrx).Methods Human PD-L1 was analyzed by bioinformatics method,and primers were designed to amplify PD-L1 IgV domain based on the coding region of PD-L1 gene registered in NCBI GenBank database. PCR amplification was carried out with pENTERPD-L1 plasmid as template,and then cloned into yeast two-hybrid bait vector pGBKT7. The recombinant bait plasmid and pGBKT7 empty vector were transformed into Y2HGold yeast cells respectively,and the PD-L1 IgV gene and its expression were detected by PCR and Western blot;Meanwhile,the protein toxicity and self-activation of PD-L1 IgV were detected,and the interaction between PD-L1 IgV and hTrx was detected by drip plate method.Results The bioinformatics analysis results of PD-L1 were consistent with related reports. The recombinant bait plasmid pGBKT7-PD-L1 IgV was correctly constructed,and Y2HGold positive clone was obtained,in which PD-L1 IgV was stably expressed. The empty vector pGBKT7 and recombinant bait plasmid pGBKT7-PD-L1 IgV grew well on SD/-Trp and SD/-Trp/X-α-Gal plates with the same colony size and number and white colony,but they did not grow on SD/-Trp/X-α-Gal/AbA plates,which indicated that PD-L1 IgV protein had no toxicity and no self-activation effect on yeast. The results of drip plates test showed that all experimental groups grew well on SD/-Trp/-Leu plate,while only positive control group grew on SD/-Trp/-Leu/X-α-Gal/AbA plate and showed blue color,which indicated that bait protein PD-L1 IgV and hTrx did not self-activate,and there was no interaction between them.Conclusion Recombinant human PD-L1 IgV bait plasmid was successfully constructed. PD-L1 IgV protein showed no toxicity and self-activation effect on yeast cells,and there was no interaction between PD-L1 IgV and hTrx. Subsequently,hTrx can be used to construct a peptide aptamer library,from which peptide aptamers that specifically bind to PD-L1 IgV can be screened.