Programmed Death Ligand Research Articles

IL-4 Downregulates PD-L1 Level Via SOCS1 Upregulation-Induced JNK Deactivation to Enhance Antitumor Immunity in In Vitro Colorectal Cancer.

Interleukin-4 (IL-4) controls cell growth and immune system regulation in tumorigenesis and can inhibit the growth of colon cancer cell lines, but the possible mechanism is unclear. In this study, we investigated the possible mechanism of IL-4 in colorectal cancer (CRC) through in vitro experiments. CRC cells received treatment with IL-4 (50 ng/mL), investigating the suppressor of cytokine signaling 1 (SOCS1)-related mechanism underlying the role of IL-4 in the progression and immunosuppression of CRC. The malignant processes of CRC cells and CD8+T cell-mediated immune response in CRC cells were determined by CCK-8, Transwell, wound healing, and flow cytometry assays. Programmed death ligand 1 (PD-L1), SOCS1 expressions, and c-Jun N-terminal kinase (JNK) activation in CRC cells were analyzed by quantitative reverse transcription polymerase chain reaction and/or Western blot. IL-4 repressed the malignant processes, yet promoted the apoptosis of CRC cells. Besides, IL-4 downregulated PD-L1 level, upregulated SOCS1 level, and restrained JNK activation in CRC cells, while enhancing CRC cell-killing effect of CD8+T cells. IL-4-induced effects on the aforementioned malignant processes of CRC cells and the killing effect of CD8+T cells toward CRC cells were all reversed when SOCS1 was knocked down in the CRC cells. IL-4 downregulates PD-L1 level via SOCS1 upregulation-induced JNK deactivation to enhance antitumor immunity in in vitro CRC. The study provides a theoretical basis for the clinical application of IL-4 in antitumor immunity in CRC.

Spatial heterogeneity of infiltrating immune cells in the tumor microenvironment of non-small cell lung cancer

Tumor-infiltrating lymphocytes (TILs) are essential components of the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). Still, it is difficult to describe due to their heterogeneity. In this study, five cell markers from NSCLC patients were analyzed. We segmented tumor cells (TCs) and TILs using Efficientnet-B3 and explored their quantitative information and spatial distribution. After that, we simulated multiplex immunohistochemistry (mIHC) by overlapping continuous single chromogenic IHCs slices. As a result, the proportion and the density of programmed cell death-ligand 1 (PD-L1)-positive TCs were the highest in the core. CD8+ T cells were the closest to the tumor (median distance: 41.71 μm), while PD-1+T cells were the most distant (median distance: 62.2μm), and our study found that most lymphocytes clustered together within the peritumoral range of 10-30 μm where cross-talk with TCs could be achieved. We also found that the classification of TME could be achieved using CD8+ T-cell density, which is correlated with the prognosis of patients. In addition, we achieved single chromogenic IHC slices overlap based on CD4-stained IHC slices. We explored the number and spatial distribution of cells in heterogeneous TME of NSCLC patients and achieved TME classification. We also found a way to show the co-expression of multiple molecules economically.

Efficacy and safety of lenvatinib combined with anti-PD-1 antibodies plus GEMOX chemotherapy as non-first-line systemic therapy in advanced gallbladder cancer

BackgroundLenvatinib, programmed cell death 1 (PD-1) antibodies, and gemcitabine and oxaliplatin (GEMOX) chemotherapy have shown significant antitumor activity as first-line therapy against biliary tract cancer. This study evaluated their efficacy and safety as non-first-line therapy in advanced gallbladder cancer (GBC).MethodsPatients with advanced GBC who received lenvatinib combined with anti-PD-1 antibodies and GEMOX chemotherapy as a non-first-line therapy were retrospectively analyzed. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR) and safety.ResultsA total of 36 patients with advanced GBC were included in this study. The median follow-up time was 11.53 (95% confidence interval (CI): 2.2–20.9) months, and the ORR was 36.1%. The median OS and PFS were 15.1 (95% CI: 3.2–26.9) and 6.1 (95% CI: 4.9–7.2) months, respectively. The disease control rate (DCR) and clinical benefit rate (CBR) were 75% and 61.1%, respectively. Subgroup analysis demonstrated that patients with programmed cell death-ligand 1 (PD-L1) expression had significantly longer PFS and OS than those without PD-L1 expression. Additionally, patients with a neutrophil–lymphocyte ratio (NLR) < 5.57 had a longer OS than those with an NLR ≥ 5.57. All patients experienced adverse events (AEs), with 61.1% experiencing grade 3 or 4 AEs, including myelosuppression (13.9%) and fatigue (13.3%), alanine transaminase or aspartate transaminase levels (8.3%), and diarrhea (8.3%). No grade 5 AEs were reported.ConclusionAnti-PD-1 antibodies combined with lenvatinib and GEMOX chemotherapy are effective and well-tolerated as a non-first-line therapy in advanced GBC. PD-L1 expression and baseline NLR may potentially predict treatment efficacy.

Assessment of the circulating levels of immune system checkpoint selected biomarkers in patients with lung cancer.

Lung cancer is recognized as one of the leading causes of cancer-related deaths globally, with a significant increase in incidence and intricate pathogenic mechanisms. This study examines the expression profiles of Programmed Cell Death Protein 1 (PD-1), PD-1 ligand (PDL-1), β-catenin, CD44, interleukin 6 (IL-6), and interleukin 10 (IL-10), as well as their correlations with the clinic-pathological features and diagnostic significance in lung cancer patients. The research involved lung cancer patients exhibiting various pathological characteristics, alongside demographically matched healthy controls. The expression levels of PD-1, PDL-1, β-catenin, and CD44 were analyzed using Real-Time PCR, while circulating levels of IL-6 and IL-10 were assessed through ELISA assays. This investigation focused on peripheral blood mononuclear cells (PBMC) to evaluate these factors non-invasively. Findings indicated that levels of PD-1, PDL-1, and CD44 were significantly elevated in patients compared to controls, which coincided with a decrease in β-catenin levels. Additionally, a concurrent rise in IL-6 and IL-10, both pro-inflammatory cytokines, was observed in patients, suggesting a potential regulatory role for these cytokines on the PD-1/PDL-1 axis, which may help tumors evade immune system checkpoints. The predictive value of these factors concerning lung tumors and metastasis was significant (Regression analysis). Furthermore, these markers demonstrated diagnostic potential in differentiating between patients and healthy controls, as well as between individuals with metastatic and non-metastatic tumors (ROC curve analysis). This study provides insights into the expression profiles of PD-1/PDL-1 immune system checkpoints and their regulatory factors in lung cancer, potentially paving the way for new therapeutic and diagnostic approaches.

A random survival forest-based pathomics signature classifies immunotherapy prognosis and profiles TIME and genomics in ES-SCLC patients

BackgroundSmall cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with high mortality, and only a limited subset of extensive-stage SCLC (ES-SCLC) patients demonstrate prolonged survival under chemoimmunotherapy, which warrants the exploration of reliable biomarkers. Herein, we built a machine learning-based model using pathomics features extracted from hematoxylin and eosin (H&E)-stained images to classify prognosis and explore its potential association with genomics and TIME.MethodsWe retrospectively recruited ES-SCLC patients receiving first-line chemoimmunotherapy at Nanjing Jinling Hospital between April 2020 and August 2023. Digital H&E-stained whole-slide images were acquired, and targeted next-generation sequencing, programmed death ligand-1 staining, and multiplex immunohistochemical staining for immune cells were performed on a subset of patients. A random survival forest (RSF) model encompassing clinical and pathomics features was established to predict overall survival. The function of putative genes was assessed via single-cell RNA sequencing.Results and conclusionDuring the median follow-up period of 12.12 months, 118 ES-SCLC patients receiving first-line immunotherapy were recruited. The RSF model utilizing three pathomics features and liver metastases, bone metastases, smoking status, and lactate dehydrogenase, could predict the survival of first-line chemoimmunotherapy in patients with ES-SCLC with favorable discrimination and calibration. Underlyingly, the higher RSF-Score potentially indicated more infiltration of CD8+ T cells in the stroma as well as a greater probability of MCL-1 amplification and EP300 mutation. At the single-cell level, MCL-1 was associated with TNFA-NFKB signaling and apoptosis-related processes. Hopefully, this noninvasive model could act as a biomarker for immunotherapy, potentially facilitating precision medicine in the management of ES-SCLC.

Lysosome Targeted Nanoparticle Aggregation Reverses Immunosuppressive Tumor Microenvironment for Cancer Immunotherapy.

Nanotechnology has proven its enormous application value in clinical practice. However, current research on nanomedicines mainly focuses on developing nanoparticles as delivery carriers to maximize the bioavailability of therapeutic agents, with little attention on exploring their potential to directly regulate physiological processes. In this study, inspired by the lysosomal swelling caused by excessive accumulation of undegraded substances, this work presents a lysosomal-targeting aggregated nanoparticle (LTANP) for cancer treatment. By rationally engineering surface composition, properties, and interparticle interactions, LTANP achieves efficient tumor accumulation and selective targeted aggregation in lysosomes of cancer cells, leading to unrelievable lysosomal swelling, and ultimately inducing lysosomal membrane permeabilization (LMP) of cancer cells. Further analysis shows that nanoparticle aggregation-mediated LMP can effectively trigger immunogenic cell death (ICD) by impairing autophagy-lysosome pathway, evoking robust antitumor immune responses and reversing tumor immunogenicity from "cold" to "hot" in a melanoma model. Additionally, LTANP can combine with clinically approved programmed death ligand-1 (PD-L1) antibodies to further unleash T cell-mediated antitumor immunity, significantly enhancing antitumor performance, inhibiting tumor recurrence and metastasis. This work demonstrates the potential of rationally engineered nanostructures in directly combating cancer and provides novel insights for the development of advanced nanoparticle-based cancer treatment.

Solid cancer-directed CAR T cell therapy that attacks both tumor and immunosuppressive cells via targeting PD-L1

Chimeric antigen receptor (CAR) T-cell therapy has encountered limited success in solid tumors. The lack of dependable antigens and the immunosuppressive tumor microenvironment (TME) are major challenges. Within the TME, tumor cells along with immunosuppressive cells employ an immune-evasion mechanism that upregulates programmed death ligand 1 (PD-L1) to deactivate effector T cells; this makes PD-L1 a reliable, universal target for solid tumors. We developed a novel PD-L1 CAR (MC9999) using our humanized anti-PD-L1 monoclonal antibody, designed to simultaneously target tumor and immunosuppressive cells. The antigen-specific antitumor effects of MC9999 CAR T-cells were observed consistently across four solid tumor models: breast cancer, lung cancer, melanoma, and glioblastoma multiforme (GBM). Notably, intravenous administration of MC9999 CAR T-cells eradicated intracranially established LN229 GBM tumors, suggesting penetration of the blood-brain barrier. The proof-of-concept data demonstrate the cytolytic effect of MC9999 CAR T-cells against immunosuppressive cells, including microglia HMC3 cells and M2 macrophages. Furthermore, MC9999 CAR T-cells elicited cytotoxicity against primary tumor-associated macrophages within GBM tumors. The concept of targeting both tumor and immunosuppressive cells with MC9999 was further validated using CAR T-cells derived from cancer patients. These findings establish MC9999 as a foundation for the development of effective CAR T-cell therapies against solid tumors.

The expression of immune checkpoint proteins PD-L1 and TIM3 in mouse and human head and neck squamous cell carcinoma.

The aim of this study was to examine the expression of programmed death-ligand 1 (PD-L1) and of T cell immunoglobulin and mucin domain-containing protein (TIM3) in oral epithelial dysplasia and head and neck squamous cell carcinoma (HNSCC). Mouse HNSCC was induced with 4-nitroquinoline-1 oxide (4NQO). Oral epithelial dysplastic lesions, carcinoma in situ and HNSCC lesions were stained with anti-PD-L1 and TIM3 antibodies. The expression of PD-L1 and TIM3 in tumor cells and immune cells was semiquantitatively measured and compared. In parallel, human dysplasia and HNSCC were stained with anti-PD-L1 and anti-TIM3. The expression pattern of PD-L1+ and TIM3+ cells was further compared. In human and mouse samples both PD-L1 and TIM3 were found to be expressed in neoplastic and immune cells in HNSCC, but not in dysplasia. There was no significant difference in PD-L1 and TIM3 expression between metastatic and nonmetastatic HNSCC. We conclude that the 4NQO-induced mouse HNSCC model may be an excellent preclinical model for immune checkpoint therapy.

Efficacy and safety of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, plus chemotherapy in patients with stage IV NSCLC

IntroductionIn a phase 1 study, bintrafusp alfa demonstrated encouraging clinical activity in patients with previously treated advanced non-small cell lung cancer (NSCLC). The current study evaluated the safety and efficacy of bintrafusp alfa with chemotherapy in patients with stage IV NSCLC regardless of the programmed death-ligand 1 (PD-L1) expression status. MethodsIn this open-label, phase 1b/2 study (NCT03840915), eligible patients were assigned to one of four cohorts. Patients with previously untreated metastatic NSCLC (cohorts A, B, and C) received bintrafusp alfa with chemotherapy as first-line treatment, whereas patients whose disease progressed on prior treatment with PD-1/PD-L1 inhibitors (cohort D) received bintrafusp alfa with chemotherapy as second-line treatment. The primary objective of this study was to evaluate the safety and tolerability of bintrafusp alfa with chemotherapy. ResultsFour serious and one nonserious treatment-emergent adverse events (AEs) were considered dose-limiting toxicities, none of which were assessed as related to bintrafusp alfa by the investigator. Any-grade bintrafusp alfa-related AEs occurred in 20.7% of patients in cohorts A+B+C and in 16.7% of patients in cohort D. Keratoacanthoma was the most common transforming growth factor-β inhibition-mediated skin lesion (cohorts A+B+C: 12.1% and cohort D: 8.3%). In cohorts A+B+C the overall response rate was 48.3% and in patients with PD-L1 tumor proportion score of ≥50.0% it was 71.4%. Based on an interim analysis, the data were considered mature, and no further analysis has been planned. ConclusionBintrafusp alfa with chemotherapy demonstrated a manageable safety profile and encouraging clinical activity in patients with stage IV NSCLC.

Label-Free Detection of Programmed Death-Ligand 1 for Prognosis Using a Truncated Aptamer and SYBR Green I.

The rapid and accurate detection of programmed death-ligand 1 (PD-L1) expression is of great value in the diagnosis and treatment of tumors. ELISA-based traditional method is the gold standard for protein detection, but there are still some shortcomings, especially the antigen-antibody dependence, greatly increased the detection time and cost. This work constructed a label-free fluorescent probe for rapid and sensitive detection of PD-L1 using a truncated aptamer as recognition molecules and double-stranded DNA specific dyes (SYBR Green I) as signal units. After a series of optimization conditions, this probe has good detection capability for PD-L1 in buffer solution with the detection limit as low as 0.68 ng/mL. Due to the specific recognition ability of aptamer and target, this method also has good selectivity for PD-L1 detection. The recovery of PD-L1 in human serum samples ranges from 86.20 to 96.36%. Compared with other methods, this strategy does not need to be marked, and does not need other complex design and purification process, but simple operation process and strong anti-interference ability. The whole detection process can be completed within 20min and has good application prospect. This work will provide reference for drug dosage and prognosis evaluation of specific tumor therapy.

Clinical Outcomes of Maintenance Durvalumab After Definitive Concurrent Chemoradiotherapy in Unresectable Locally Advanced Stage III NSCLC According to EGFR and ALK Status: Korean Cancer Study Group LU-22-18

IntroductionThe role of maintenance durvalumab after definitive concurrent chemoradiotherapy (CCRT) in unresectable locally advanced NSCLC with EGFR mutation or ALK translocation remains unclear. We compared the effectiveness of durvalumab maintenance therapy in groups with EGFR/ALK wild-type versus those with EGFR or ALK mutations. MethodsIn this retrospective multicenter observational study, patients with locally advanced NSCLC without progression after CCRT followed by maintenance durvalumab and available molecular test results (EGFR and ALK) were eligible. The primary objective was to compare progression-free survival (PFS) between EGFR/ALK wild-type and EGFR or ALK mutant NSCLC. Secondary objectives include overall survival according to EGFR or ALK mutation and programmed death-ligand 1 (PD-L1) expression. ResultsAmong 339 patients, 279 had wild-type EGFR/ALK, 41 had EGFR mutations and 19 had ALK translocations. The median age was 68 years with 276 male individuals (81.4%) and 63 female individuals (18.6%), 165 (49.3%) had adenocarcinoma, 149 (44.5%) had squamous cell carcinoma, and 21 (6.3%) had other histologic types, 120 (35.4%) had stage IIIA, 168 (49.6%) stage IIIB, and 51 (15.0%) had stage IIIC. Most of the patients (n = 288, 85%) achieved partial response to CCRT, two (0.6%) had a complete response, and 49 patients (14.4%) had stable disease. Excluding four patients with unknown PD-L1 tumor proportion score (TPS), 16 (4.8%) had a PD-L1 TPS of 0, 168 (50.1%) had 1 to 49, and 151 (45.1%) had 50 or higher. The median PFS was 21.4 months (95% confidence interval [CI]: 17.3–25.3) for the EGFR/ALK wild-type group and 21.0 months (95% CI: 15.7–not available [NA]) for the EGFR or ALK mutant group with no significant difference (p = 0.74). Significant differences occurred in PFS on the basis of PD-L1 expression with values of 13.6 (95% CI: 10.5–NA), 18.7 (95% CI: 15.1–26.9), and 24.7 (95% CI: 20.7–NA) months for TPS of 0, 1–49, and 50 or higher, respectively (p = 0.02). ConclusionsDurvalumab maintenance therapy after definitive CCRT in unresectable locally advanced NSCLC patients with EGFR or ALK mutation demonstrates comparable clinical outcomes to those with wild-type EGFR/ALK when PD-L1 expression is present.

Cancer cell-specific PD-L1 expression is a predictor of poor outcome in patients with locally advanced oral cavity squamous cell carcinoma

BackgroundLocally advanced oral cavity squamous cell carcinoma (OCSCC) presents a significant clinical challenge despite being partially responsive to standard treatment modalities. This study investigates the prognostic implications of programmed death-ligand...

Correlation of programmed death-ligand 1 expression in tumour cells between diagnostic small biopsies performed by radial EBUS and surgical specimens of peripheral lung cancer

Background and objectiveExpression of programmed death-ligand 1 (PD-L1) in tumour cells (TCs) is predictive of immunotherapy efficacy in non-small cell lung cancer (NSCLC). Small biopsy samples collected by bronchoscopy are...

Towards novel small-molecule inhibitors blocking PD-1/PD-L1 pathway: From explainable machine learning models to molecular dynamics simulation

Molecular design of small-molecule inhibitors targeting programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway has been recognized as an active research area by the clinical success of cancer immunotherapy. In recent years, using machine learning (ML) methods to accelerate drug design have been confirmed. However, the black box character of ML methods makes model interpretation and ligands optimization obscured. Herein, five explainable ML models were constructed by integrating five ML models with the SHAP method, where these ML models were pretrained with >4000 molecules and their R2 ranged from 0.835 to 0.86 on test set. Subsequently, the explainable ML models were employed to identify the relationship between fragments and bio-activity of a small molecule inhibitor BMS-1166, leading to the modification of BMS-1166 into 60 novel compounds. After consensus docking and ADMET test, 3 small molecules (C27, C52 and C54) with better docking scores and lower toxicity than BMS-1166 were screened out further. Finally, the improved binding affinity of C27, C52 to the PD-L1 dimer was validated by the MD simulation. Overall, this work proposed an efficient protocol on the basis of explainable ML models for designing small-molecule inhibitors targeting PD-1/PD-L1 pathway in a rational way.

Novel bispecific antibody-drug conjugate targeting PD-L1 and B7-H3 enhances antitumor efficacy and promotes immune-mediated antitumor responses

BackgroundAntibody-drug conjugates (ADCs) offer a promising approach, combining monoclonal antibodies with chemotherapeutic drugs to target cancer cells effectively while minimizing toxicity.MethodsThis study examined the therapeutic efficacy and potential mechanisms of...

The relationship between sarcopenia and metabolic parameters of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and the prognostic value of sarcopenia in early-stage non-small cell lung cancer.

Patients with lung cancer face a heightened risk of developing sarcopenia. Despite this known risk, the impact of sarcopenia on the long-term prognosis of lung cancer patients, specifically concerning progression-free survival (PFS) and overall survival (OS), remains unclear. The primary objective of our study was to examine the correlation between metabolic parameters derived from 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and sarcopenia, as well as the prognostic value of sarcopenia in patients with surgically resected early-stage non-small cell lung cancer (NSCLC). In this retrospective cross-sectional study, we analyzed 187 NSCLC patients who underwent 18F-FDG PET/CT at the First Affiliated Hospital of Soochow University between March 2019 and October 2023. Patients were divided into two groups based on the presence (n=46) or absence (n=141) of sarcopenia. The correlation between sarcopenia, metabolic parameters, and patient characteristics was evaluated using chi-square and Mann-Whitney U tests. Survival analyses, including PFS and OS, were conducted using Kaplan-Meier analysis and Cox proportional hazards regression. Based on sarcopenia, metabolic parameters and patient characteristics, patients were classified into high-risk (n=28), intermediate-risk (n=121), and low-risk (n=38) groups. Our analysis identified gender, body mass index (BMI), psoas Hounsfield unit (HU), and maximum standardized uptake value of the psoas major muscle (SUVmax-Muscle) as independent predictors of sarcopenia (P<0.05 for all). A nomogram model, utilizing these parameters, was constructed to predict sarcopenia. Survival analysis further demonstrated that total lesion glycolysis [hazard ratio (HR) =2.499; 95% confidence interval (CI): 2.014-3.267; P=0.016], sarcopenia (HR =3.323; 95% CI: 1.748-6.316; P<0.001), and programmed death ligand-1 (PD-L1) expression (HR =0.093; 95% CI: 0.012-0.698; P=0.021) emerged as independent predictors of OS in early-stage NSCLC. Notably, patients categorized as high-risk, characterized by elevated total lesion glycolysis, presence of sarcopenia, and PD-L1 positivity, exhibited a significantly poorer prognosis compared to the intermediate-risk (P<0.05) and low-risk groups (P<0.05). Our findings indicated an inverse relationship between SUVmax-Muscle or psoas HU with the incidence of sarcopenia in NSCLC patients. Additionally, total lesion glycolysis, sarcopenia, and PD-L1 expression were identified as independent prognostic factors for OS in early-stage NSCLC. The risk stratification model, incorporating total lesion glycolysis, sarcopenia, and PD-L1 expression, assumed a pivotal role in guiding personalized therapy decisions and post-treatment monitoring.

PD1CD28 chimeric molecule enhances EGFRvⅢ specific CAR-T cells in xenograft experiments in mouse models.

Over the years, CAR-T cell therapy has achieved remarkable success in treating hematological malignancies. However, this efficacy has not been replicated in the context of glioblastoma (GBM). In this study, a PD1CD28 chimeric molecule was introduced into EGFRvⅢ-directed CAR-T cells, generating EGFRvⅢ-P2A-PD1CD28 CAR-T cells. Notably, this modification significantly increased IL-2 secretion and enhanced antigen-dependent activation of CAR-T cells, especially when programmed cell death ligand 1 (PD-L1) was present in vitro. In addition, the in vivo xenograft experiments revealed that the PD1CD28 chimeric molecule played a pivotal role in reducing recurrence rates, effectively controlling recurrent tumor volume, and ultimately prolonging the survival of mice. Collectively, these findings suggest that EGFRvⅢ-directed CAR-T cells co-expressing the PD1CD28 chimeric molecule have the potential to significantly enhance the treatment efficacy against GBM.

Clinicopathologic features and tumor immune microenvironment of lymphocyte-rich hepatocellular carcinoma

Lymphocyte-rich hepatocellular carcinoma (LR-HCC) is a rare variant of HCC characterized by pronounced lymphoid infiltration, providing an opportunity to explore the tumor immune microenvironment (TIME) and its potential impact on disease progression and therapy. This study aimed to describe the clinicopathological features and TIME components of LR-HCC to inform more effective treatment strategies. In this study, we present five novel cases of LR-HCC alongside a comprehensive retrospective analysis of 136 previously documented cases. Immunohistochemical evaluation was utilized to systematically assess TIME components and immune checkpoint inhibitor (ICI) targets. Our findings demonstrated a significant predominance of CD3+ T cells over CD20+ B cells (1.5:1, P < 0.001) and a higher frequency of CD8+ cytotoxic T cells compared to Foxp3+ regulatory T cells (2.4:1, P < 0.001), indicating an immune landscape potentially favorable for immunotherapeutic interventions. Programmed cell death ligand 1 (PD-L1) expression was detected in three out of five cases using the VENTANA SP263 assay, suggesting potential responsiveness to ICIs. A pooled analysis of 38 cases showed a 5-year overall survival rate of 73.6 %, which is notably lower than previously reported rates (>90 %), with 29.4 % of patients experiencing postoperative recurrence or lymph node metastasis. Multivariate analysis identified tumor size as an independent predictor of overall survival. These findings emphasize the relevance of TIME characteristics in understanding LR-HCC and point to promising avenues for targeted and immune-based therapies, contributing to the optimization of clinical management for this distinct cancer subtype.

Regulatory Role of IL6 in Immune-Related Adverse Events during Checkpoint Inhibitor Treatment in Melanoma

The landscape of clinical management for metastatic melanoma (MM) and other solid tumors has been modernized by the advent of immune checkpoint inhibitors (ICI), including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. While these agents demonstrate efficacy in suppressing tumor growth, they also lead to immune-related adverse events (irAEs), resulting in the exacerbation of autoimmune diseases such as rheumatoid arthritis (RA), ulcerative colitis (UC), and Crohn’s disease (CD). The immune checkpoint inhibitors offer promising advancements in the treatment of melanoma and other cancers, but they also present significant challenges related to irAEs and autoimmune diseases. Ongoing research is crucial to better understand these challenges and develop strategies for mitigating adverse effects while maximizing therapeutic benefits. In this manuscript, we addressed this challenge using network-based approaches by constructing and analyzing the molecular and signaling networks associated with tumor-immune crosstalk. Our analysis revealed that IL6 is the key regulator responsible for irAEs during ICI therapies. Furthermore, we conducted an integrative network and molecular-level analysis, including virtual screening, of drug libraries, such as the Collection of Open Natural Products (COCONUT) and the Zinc15 FDA-approved library, to identify potential IL6 inhibitors. Subsequently, the compound amprenavir was identified as the best molecule that may disrupt essential interactions between IL6 and IL6R, which are responsible for initiating the signaling cascades underlying irAEs in ICI therapies.

Association between programmed cell death ligand-1 expression in patients with cervical cancer and apparent diffusion coefficient values: a promising tool for patient´s immunotherapy selection.

To investigate the associations between apparent diffusion coefficient (ADC) values extracted from three different region of interest (ROI) position approaches and programmed cell death ligand-1 (PD-L1) expression, and evaluate the performance of the nomogram established based on ADC values and clinicopathological parameters in predicting PD-L1 expression in cervical cancer (CC) patients. Through retrospective recruitment, a training cohort of 683 CC patients was created, and a validation cohort of 332 CC patients was prospectively recruited. ROIs were delineated using three different methods to measure the mean ADC (ADCmean), single-section ADC (ADCss), and the minimum ADC of tumors (ADCmin). Logistic regression was employed to identify independent factors related to PD-L1 expression. A nomogram was drawn based on ADC values combined with clinicopathological features, its discrimination and calibration performances were estimated using the area under the curve (AUC) of receiver operating characteristic and calibration curve. The clinical benefits were evaluated by decision curve analysis. The ADCmin independently correlated with PD-L1 expression. The nomogram constructed with ADCmin and other independent clinicopathological-related factors: FIGO staging, pathological grade, parametrial invasion, and lymph node status demonstrated excellent diagnostic performance (AUC = 0.912 and 0.903, respectively), good calibration capacities, and greater net benefits compared to the clinicopathological model in both the training and validation cohorts. ADCmin independently correlated PD-L1 expression, and the nomogram established with ADCmin and clinicopathological independent prognostic factors had a strong predictive performance for PD-L1 expression, thereby serving as a promising tool for selecting cases eligible for immunotherapy. The minimum ADC can serve as a reliable imaging biomarker related to PD-L1 expression; the established nomogram combines the minimum ADC and clinicopathological factors that can assist clinical immunotherapy decisions.