Programmed Death-ligand 1 Expression Research Articles

Does chemotherapy regimen matter for first-line immunochemotherapy in low programmed cell death ligand 1 (PD-L1)-expressing esophageal squamous cell carcinoma (ESCC)? A systemic review and meta-analysis.

395 Background: Anti-programmed death 1 (PD-1) therapy plus chemotherapy has become standard first-line therapy for patients with high PD-L1-expressing advanced ESCC. The benefit for patients with low PD-L1-expressing ESCC remains debatable. Methods: Eligible studies were phase III trials investigating anti-PD-1/PD-L1 therapy plus chemotherapy (immunochemotherapy) vs chemotherapy as first-line therapy of advanced ESCC. Study-level pooled analyses of hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS) with corresponding 95% confidence intervals (CI), were used to compare the different groups in random-effects model. PD-L1 expression levels with tumor proportion score (TPS) ≥ 1% vs < 1%, tumor area positivity (TAP) ≥ 10% vs < 10%, and combined positive score (CPS) ≥ 10 vs < 10 were collectively categorized as high vs low PD-L1 expression. The impact of two different chemotherapy regimens, TP (paclitaxel plus platinum) and PF (platinum pus fluoropyrimidine), stratified by PD-L1 expression levels, on the survival benefit of immunochemotherapy vs chemotherapy was investigated. Results: Eight randomized controlled trials including 4733 subjects were enrolled. Immunochemotherapy vs chemotherapy was associated with significantly improved PFS and OS irrespective of PD-L1 expression levels or chemotherapy regimens (Table). The PFS and OS benefits were more pronounced in high PD-L1 group than low PD-L1 group. In patients with high PD-L1 expression, the PFS and OS benefits were not significantly different between two chemotherapy regimen subgroups. However, in patients with low PD-L1 expression, the PFS benefit was more significant in TP subgroup than PF subgroup, and OS benefit trended to be in favor of TP subgroup. Conclusions: The addition of anti-PD-1/PD-L1 therapy to TP chemotherapy may associate with more significant survival benefit than to PF chemotherapy in advanced ESCC with low PD-L1 expression. Population PFS (immunochemotherapy vs chemotherapy) OS (immunochemotherapy vs chemotherapy) HR(95% CI) P value(subgroup differences) HR(95% CI) P value(subgroup differences) All patients 0.63 (0.57-0.69) 0.69 (0.64-0.74) High PD-L1 group 0.54 (0.49-0.60) P < 0.01 0.60 (0.53-0.67) P < 0.01 Low PD-L1 group 0.71 (0.62-0.81) 0.78 (0.70-0.87) TP group 0.56 (0.50-0.62) P < 0.01 0.66 (0.59-0.74) P = 0.32 PF group 0.68 (0.62-0.75) 0.72 (0.65-0.79) Among high PD-L1 patients TP subgroup 0.56 (0.45-0.69) P = 0.75 0.60 (0.46-0.78) P = 0.90 PF subgroup 0.53 (0.45-0.62) 0.59 (0.50-0.69) Among low PD-L1 patients TP subgroup 0.59 (0.48-0.74) P = 0.01 0.72 (0.55-0.93) P = 0.32 PF subgroup 0.82 (0.72-0.94) 0.84 (0.72-0.97)

Relationship between PD-L1 expression and the number of biopsy specimens in advanced gastric cancer.

481 Background: Programmed cell death ligand 1 (PD-L1) expression shows spatial heterogeneity in gastric cancer. Compared with single biopsies, multiple biopsies may provide reliable PD-L1 expression results. However, the optimal number of biopsy specimens remains unclear. This study aimed to assess the relationship between PD-L1 expression and the number of biopsy specimens in advanced gastric cancer. Methods: We retrospectively analyzed patients with advanced gastric cancer who received first-line chemotherapy at a single institution between December 2021 and June 2024. Those in whom PD-L1 expression was evaluated using tumor-containing biopsy specimens were included. PD-L1 expression was measured using the Dako PD-L1 IHC 28-8 pharmDx assay. PD-L1 positivity was defined as a combined positive score of ≥5. The association between PD-L1 positivity and the number of biopsy specimens was tested using the chi-square or Fisher’s exact test. Results: Of the 183 patients screened, 110 were included. The patient characteristics were as follows: median age, 71 (range: 34–87) years; sex (male/female), 75/35; primary site (gastric/gastroesophageal junction), 102/8; and histological type (diffuse/intestinal/other), 59/34/17. The PD-L1 positivity prevalence was 71.8%. In 97 patients, human epidermal growth factor receptor 2 (HER2) expression was detected in the same specimens as PD-L1, with a HER2-positive rate of 14.4%. The mean numbers of biopsy and tumor-containing biopsy specimens were 5.14 (range: 2–10) and 4.25 (range: 1–10), respectively. The PD-L1 positivity prevalence was significantly higher when the number of biopsy specimens was ≥5 compared with ≤4 (77.5% vs 56.7%, P =0.03; Table). The same trend was observed according to the histological type (diffuse type, 75.0% vs. 46.7%, P =0.04; intestinal type, 79.2% vs. 60.0%, P =0.39). In HER2-negative cases, PD-L1 positivity was significantly more prevalent when the number of biopsy specimens was ≥5 compared with ≤4 (83.6% vs 54.5%, P =0.006; Table). However, there was no such difference in HER2-positive cases (54.4% vs 66.7%, P =1). Conclusions: The data suggest that collecting at least five biopsy specimens increases the likelihood of identifying PD-L1 positivity in advanced gastric cancer, particularly in HER2-negative cases. This approach may improve PD-L1 evaluation accuracy and lead to better treatment decisions. Relationship between the number of biopsy specimens and PD-L1 positivity. Number of biopsy specimens PD-L1 positivity (%) PD-L1 negativity (%) P value Overall 0.03 ≥5 77.5 22.5 ≤4 56.7 43.3 HER2-negative 0.006 ≥5 83.6 16.4 ≤4 54.5 45.5

Impact of tislelizumab + chemotherapy versus placebo + chemotherapy on patient-reported symptoms and overall survival (OS) by programmed death-ligand 1 (PD-L1) expression in advanced or metastatic esophageal squamous cell carcinoma (ESCC): A post hoc analysis of the RATIONALE-306 trial.

366 Background: While improved survival has been previously demonstrated, the impact of immunotherapy on HRQoL in ESCC has not been well examined. Traditional PRO-based analyses in oncology trials, such as time to deterioration (TTD) and mixed models for repeated measures (MMRMs), are limited by discounting recurrent PRO events. Thus, we applied a 3-component joint model (JM) framework to define more clinically interpretable associations between patient-reported symptoms, treatment effects, and OS among subgroups of patients with ESCC from RATIONALE-306, which met its primary endpoint, with PD-L1 expression of ≥1%, ≥5%, and ≥10%. Methods: The final analytic sample included 226 patients in the tislelizumab + chemotherapy arm (T+C), 242 in the placebo + chemotherapy arm (P+C) for PD-L1 ≥1%, 113 in the T+C arm and 103 in the P+C arm for PD-L1 ≥5%, and 168 in the T+C arm and 178 in the P+C arm for PD-L1 ≥10%.From EORTC QLQ-C30 and OES18, 7 keysymptom domains were modeled (GHS, physical functioning, fatigue, dysphagia, pain, reflux, dietary restrictions). PRO data were collected at baseline and at every treatment cycle (up to 6 cycles), then every other cycle, and at safety follow-up, and change from baseline (CFBL) was analyzed. The joint model comprised three components: 1) linear mixed model predicting CFBL symptom scores; 2) Cox proportional hazard model (CPH) for time to OS; and 3) frailty (random effects for recurrent deterioration events [RDEs]) CPH model for time to PRO-based RDEs. Osoba (1998) 10-point threshold was used to define RDEs. Results: Adjusted completion rates were >90% in the ITT population for both arms. Significant T+C treatment effects wereobserved for physical functioning in PD-L1 ≥5% ( P =0.0476), and pain in PD-L1 ≥1% ( P =0.0028) and PD-L1 ≥5% ( P =0.0149) subgroups, but not in PD-L1 ≥10%. For other 5 symptoms (ie, GHS, fatigue, reflux, dysphagia, dietary restrictions), there were no statistically significant differences between treatment arms. However, T+C was associated with significant reductions in the risk of death across all 7 key symptoms and PD-L1 subgroups. As one example, with respect to interaction between pain and OS, T+C was associated with a 22% (HR, 0.78 [95% CI, 0.652-0.931]), 33% (HR, 0.67 [95% CI, 0.515-0.860]), and 47% (HR, 0.50 [95% CI, 0.344-0.720]) reduction in the risk of death in PD-L1 ≥1%, ≥5%, and ≥10%, respectively compared with P+C. Conclusions: In this analysis, the addition of tislelizumab to chemotherapy was associated with significantly less deterioration in multiple PRO symptoms including physical functioning and pain, alongside a lower risk of death, after adjusting for recurring deterioration events using a frailty model across multiple PD-L1 expression subgroups.

Impact of tislelizumab + chemotherapy versus placebo + chemotherapy on patient-reported symptoms and disease progression by programmed death-ligand 1 expression in gastroesophageal adenocarcinoma: A post hoc analysis of the RATIONALE-305 trial.

365 Background: The relationship between patient-reported outcome (PRO)-based symptom scores, recurrent PRO-based symptomatic deterioration events (RDEs), and terminal events such as progression-free survival (PFS) are rarely examined in the oncology therapeutic domain. Thus, we applied a 3-component joint model (JM) framework aiming to illuminate more clinically interpretable associations between PRO-based treatment effects, RDEs, and PFS among subgroups of patients with programmed death-ligand 1 (PD-L1) expression of ≥1%, ≥5%, and ≥10%. Methods: The final analytic sample included 378 patients in the tislelizumab + chemotherapy arm (T+C) vs 401 in the placebo + chemotherapy arm (P+C) for the PD-L1 ≥1% subgroup, 238 in the T+C arm vs 237 in the P+C for the PD-L1 ≥5% subgroup, and 118 in the T+C arm vs 125 in the P+C arm for the PD-L1 ≥10% subgroup. Symptom domain scores from the EORTC QLQ-C30 and QLQ-STO22 symptom were modeled. Change from baseline (CFBL) in each domain was analyzed every cycle up to cycle 6, then every other cycle thereafter (up to cycle 25). The joint model was applied to all PD-L1 subgroups and comprised three components: 1) linear mixed model (LMM) predicting CFBL symptom scores, 2) Cox proportional hazard (CPH) model for disease progression (PFS as terminal event), and 3) frailty (random effects for RDEs) CPH model for time to PRO-based RDEs. Osoba’s 10-point threshold was used to define RDEs. Results: In the LMM, significant treatment efficacy for the T+C arm compared with the P+C arm was observed for the GHS/QoL ( P =0.0080) and dietary restriction scores ( P =0.0475) in the PD-L1 ≥5% subgroup. In the PD-L1 ≥1% subgroup, compared with the P+C arm, the T+C arm was associated with less worsening in pain/discomfort ( P =0.0376), upper gastrointestinal symptoms ( P =0.0088), and dietary restrictions ( P =0.0352). In the CPH model, the average hazard ratio indicated that compared with the P+C arm, the T+C arm was associated with a reduction in risk of disease progression across all PRO domains and PD-L1 subgroups. Lastly, the PRO-based RDE frailty predictions were strongly associated with PFS risk in the PD-L1 ≥1% and ≥5% subgroups for GHS/QoL, and in the PD-L1 ≥1% subgroup for physical functioning, fatigue, dysphagia-odynophagia, pain/discomfort, and dietary restrictions, as well as for pain/discomfort and dietary restrictions in the PD-L1 ≥5% subgroup. Conclusions: Through the 3-component JM, PRO-based effects were detected and demonstrated strong associations between PRO-based RDEs, and investigator-assessed PFS among varying PD-L1 expression levels. This framework may be a promising alternative for analyzing and interpreting PRO data in the context of PFS.

The prevalence of PD-L1 expression in patients with advanced oesophageal cancer: the EXCEED observational study

AimsThere are limited data on programmed death ligand 1 (PD-L1) expression in oesophageal cancer (OC) from multicentre studies conducted across China. We aimed to determine the prevalence of high PD-L1...

Comparison of PD-L1 Expression Between Preoperative Biopsy Specimens and Surgical Specimens in Non-Small Cell Lung Cancer

Background: Recent advances in perioperative immunotherapies have led to a new era in the perioperative treatment of resectable, non-small cell lung cancer (NSCLC). Although the choice of neoadjuvant, adjuvant or perioperative immunotherapy remains controversial, few reports have compared programmed death ligand-1 (PD-L1) expression as a biomarker between preoperative biopsy specimens and surgical specimens. Methods: We retrospectively reviewed consecutive patients with NSCLC whose preoperative biopsy specimens and surgical specimens were tested for PD-L1 (22C3) and PD-L1 (SP263), respectively, from June 2022 to February 2024. The three categorical classifications of PD-L1 expression (negative [<1%], low [1–49%], and high [≥50%]) were compared between the two tests. Results: Of the 33 patients, 13 patients had negative PD-L1 expression, 9 patients had low PD-L1 expression and 11 patients had high PD-L1 expression with preoperative biopsy specimens, while 18 patients had negative PD-L1 expression, 10 patients had low PD-L1 expression and 5 patients had high PD-L1 expression with surgical specimens. The concordance rate for the three categorical classifications of PD-L1 expression between the preoperative biopsy specimens and surgical specimens was 57.6%. Conclusions: PD-L1 expression may differ between preoperative biopsy specimens and surgical specimens. PD-L1 expression evaluated using small biopsy specimens may be largely influenced by chance due to intra-tumoral heterogeneity.

Prediction of immunotherapy response in nasopharyngeal carcinoma: a comparative study using MRI-based radiomics signature and programmed cell death ligand 1 expression score.

To compare an MRI-based radiomics signature with the programmed cell death ligand 1 (PD-L1) expression score for predicting immunotherapy response in nasopharyngeal carcinoma (NPC). Consecutive patients with NPC who received immunotherapy between January 2019 and June 2022 were divided into training (n = 111) and validation (n = 66) sets. Tumor radiomics features were extracted from pretreatment MR images. PD-L1 combined positive score (CPS) was calculated using immunohistochemistry. The least absolute shrinkage and selection operator (LASSO) algorithm was used for feature selection and radiomics signature construction. Receiver operating characteristic (ROC) curve analysis was performed to assess prediction performance. A total of eleven radiomics features with the greatest discrimination capability were identified by the LASSO algorithm to construct the radiomics signature. In predicting patients with objective response to immunotherapy, radiomics score (Rd-score) yielded a significantly higher area under the ROC curve than that of CPS in both the training (0.790 vs. 0.645, p = 0.025) and the validation (0.735 vs. 0.608, p = 0.038) sets. Multivariate analysis identified the Rd-score as an independent influencing factor in predicting immunotherapy response (odds ratio = 19.963, p < 0.001). Kaplan-Meier analysis indicated that patients with Rd-score ≥ 0.5 showed longer progression-free survival than patients with Rd-score < 0.5 (log-rank p < 0.01). An MRI-based radiomics signature demonstrated greater efficacy than the PD-L1 expression score in predicting immunotherapy response in patients with NPC. Question How does an MRI-based radiomics signature compare with the programmed cell death ligand 1 expression score for predicting immunotherapy response in nasopharyngeal carcinoma? Findings The MRI-based radiomics signature demonstrated superior predictive value compared with programmed cell death ligand 1 expression score in identifying immunotherapy responders. Clinical relevance MRI-based radiomics are a promising novel noninvasive tool for predicting immunotherapy outcomes in nasopharyngeal carcinoma.

Fluorouracil enhances the anti-pancreatic cancer effect of anti-PD-L1 antibodies via up-regulating the expression of PD-L1 in cancer cells.

Pancreatic cancer is characterized by occult onset, low early diagnosis rate, rapid progress, and poor prognosis. Due to the low response rate and low programmed cell death ligand 1 (PD-L1) expression in pancreatic cancer, the therapeutic application of PL-L1 inhibitors in pancreatic cancer is greatly limited. In vitro studies showed that the expression of PD-L1 increased in pancreatic cancer cells stimulated by fluorouracil (5-FU). We aim to explore the combined effect of 5-FU and anti-PD-L1 antibodies and to provide a reference for the clinical application of PD-L1 antibodies in pancreatic cancer. In the current study, male BALB/c mice were adopted to construct a tumor-bearing model of pancreatic cancer cells. 5-FU and anti-mouse PD-L1 antibodies were combined and administered to evaluate their synergistic effects. The enhancing immune cytotoxicity effect of 5-FU sensitizing the anti-PD-L1 antibody in vivo and in vitro was analyzed by immunohistochemistry and western blot assays. Results showed that 5-FU and anti-PD-L1 antibody combination increased the expression of PD-L1 and IFN-γ, and infiltration of CD8+ T lymphocytes in pancreatic xenograft tumor tissues, which was proven by immunohistochemistry and western analysis. Moreover, the combination with the 5-FU remarkably enhanced the immune cytotoxicity of anti-PD-L1 antibodies in mice. In vitro analysis demonstrates that 5-FU increases the expression of PD-L1 on the surface of pancreatic cancer cell lines via up-regulating nuclear factor kappa B (NF-κB) and Protein kinase B (AKT) pathways. This synergistic effect could be abolished by NF-κB and AKT inhibitors.

Lutetium-177 labeled iPD-L1 as a novel immunomodulator for cancer-targeted radiotherapy

BackgroundCancer immunotherapy is a relatively new approach to cancer treatment. Peptides that target specific pathways and cells involved in immunomodulation can potentially improve the efficacy of cancer therapy. Recently, we reported iPD-L1 as a novel inhibitor peptide that specifically targets the cancer cell ligand PD-L1 (programmed death ligand 1). PD-L1 is responsible for inhibiting the immune checkpoint protein PD-1 expressed by regulatory T cells. On the other hand, anti-PD-L1 immunotherapy in combination with external beam radiotherapy has shown improved outcomes in the treatment of breast and lung cancer. The aim of this research was to prepare 177Lu-labeled iPD-L1 and to preclinically evaluate its radiotherapeutic potential and role as a tumor immunomodulator by measuring macrophage activation, IL-10, TGFβ, and PD-L1 expression in 4T1 triple-negative breast cancer cells and murine 4T1 tumors after treatment with 177Lu-iPD-L1.ResultsThe iPD-L1 ligand, characterized by UPLC mass, UV-Vis, and FT-IR spectroscopies, showed a chemical purity of 99%. The 177Lu-iPD-L1 radiochemical purity was 98.9 ± 1.1%. In vitro and in vivo studies demonstrated radiotracer stability in human serum (> 97% after 24 h evaluated by radio-HPLC), adequate affinity by the PDL1 protein (IC50 = 4.21 nM), and specific detection for PD-L1 assessed in 4T1, HCT116, and AR42J cancer cells, in which PD-L1 expression was verified by immunofluorescence and Western Blot assays. After treatment with 177Lu-iPD-L1 (0.4 Bq/cell), flow cytometry results showed a significant decrease in cell viability of 4T1 cells (dead 56.2%) compared to 177LuCl3 (dead 34.2%) and untreated cells (dead 9.4%). With high tumor uptake (6.97 ± 1.04%ID) and hepatobiliary and renal clearance, lutetium-177-labeled iPD-L1 delivered a tumor dose of 27 Gy/37 MBq and less than 0.36 Gy/37 MBq to non-source organs. PD-L1 positive tumors showed a significant increase in activated macrophages, PD-L1, IL-10, and TGFβ expression levels after 177Lu-iPD-L1 treatment as evaluated by ELISA assay and immunohistochemistry.ConclusionsTherefore, this study warrants further dosimetric and clinical studies to determine the immunomodulatory effect and therapeutic efficacy of 177Lu-iPD-L1 in treating PD-L1-positive tumors in combination with anti-PD-1/PD-L1 immunotherapy protocols.

C-X-C chemokine receptor type 5+CD8+ T cells as immune regulators in hepatitis Be antigen-positive chronic hepatitis B under interferon-alpha treatment

BACKGROUND C-X-C chemokine receptor type 5 (CXCR5)+CD8+ T cells represent a unique immune subset with dual roles, functioning as cytotoxic cells in persistent viral infections while promoting B cell responses. Despite their importance, the specific role of CXCR5+CD8+ T cells in chronic hepatitis B (CHB), particularly during interferon-alpha (IFN-α) treatment, is not fully understood. This study aims to elucidate the relationship between CXCR5+CD8+ T cells and sustained serologic response (SR) in patients undergoing 48 weeks of pegylated IFN-α (peg-IFN-α) treatment for CHB. AIM To elucidate the relationship between CXCR5+CD8+ T cells and sustained SR in patients undergoing 48 weeks of peg-IFN-α treatment for CHB. METHODS This study enrolled 60 patients with hepatitis Be antigen (HBeAg)-positive CHB undergoing 48 weeks of peg-IFN-α treatment. Participants were assessed for eligibility based on criteria such as persistent HBsAg-positive status for at least six months, HBeAb-negative, hepatitis B virus DNA levels exceeding 2 × 104 copies/mL, and alanine aminotransferase (ALT) levels between 2 and 10 times the upper limit of normal. Blood samples were collected at baseline and at weeks 12, 24, 48, and a 24-week treatment-free follow-up (week 72) to measure serum interleukin (IL)-21 concentration via ELISA and to analyze CXCR5 and programmed death-ligand 1 (PD-L1) expression on CD8+ T cells by flow cytometry, CXCR5 is a chemokine receptor that directs immune cells to specific tissues, while PD-L1 is a protein that regulates immune responses by inhibiting T cell activity. RESULTS Patients with CHB exhibited significantly lower levels of circulating CXCR5+CD8+ T cells compared to healthy controls (P &lt; 0.01). Notably, CXCR5+CD8+ T cells were prominently expressed in patients who achieved sustained SR compared to non-SR (NSR). A significant correlation was observed between CXCR5 and PD-L1 expression (r = -0.189, P = 0.002). However, there was no significant correlation between serum IL-21 levels and CXCR5+CD8+ lymphocytes (r = -0.03, P = 0.625) or serum ALT levels (r = 0.026, P = 0.678). CONCLUSION The enhanced expression of CXCR5+CD8+ T cells in patients achieving HBeAg seroconversion during IFN-α treatment suggests that these cells play a crucial role in antiviral immune responses against hepatitis B. This study highlights the potential of CXCR5+CD8+ T cells as immune regulators in CHB, which may inform future therapeutic strategies to optimize antiviral treatments.

Efficacy and Safety of Immunotherapy Combined with Anlotinib as FirstLine Treatment in Older NSCLC Patients with PD-L1 Expression

Non-small cell lung cancer (NSCLC) predominantly affects older adults; these patients have significant comorbidities, making them unsuitable for chemotherapy. This study aimed to evaluate the efficacy and safety of immune checkpoint inhibitor (ICI) along with anlotinib combination therapy as a first-line treatment in older NSCLC patients with programmed death ligand-1(PD-L1) expression＜50%. We conducted a retrospective observational study including 73 patients with advanced NSCLC treated at Nanjing Brain Hospital. All patients were aged 75 years or older and received first-line systemic therapy with a combination of PD-1 inhibitors and anlotinib. Clinical data were obtained from electronic medical records and analyzed through Kaplan-Meier estimates and Cox proportional hazards models to assess progression-free survival (PFS), overall survival (OS), and the influence of different variables. The patients had a median age of 80 years. The median PFS was 9.8 months (95% CI: 7.9-11.7), and the median OS was 19.5 months (95% CI: 17.3-21.7). PD-L1 tumor proportion score (TPS) <1% (χ2=10.263, P=0.001) and absence of treatment-induced hypertension (χ2=12.804, P<0.001) were identified as independent risk factors for poor PFS. Advanced disease stage (χ2=11.900, P=0.001), PD-L1 TPS <1% (χ2=6.643, P=0.010), and having two or more chronic comorbidities (χ2=9.011, P=0.003) were independent risk factors for poor OS. Treatment-related hypertension was observed in 25% of patients and was associated with better PFS. ICI-anlotinib combination therapy showed promising efficacy and an acceptable safety profile in older NSCLC patients. Future studies involving larger populations are necessary to validate these findings and determine the potential of PD-L1 levels as a biomarker for treatment stratification.

Dual targeting PD-L1 and 4-1BB to overcome dendritic cell-mediated lenalidomide resistance in follicular lymphoma

Immunomodulatory agent lenalidomide is effective in treating follicular lymphoma (FL). We conducted the first trial of immunotherapy rituximab plus lenalidomide in newly diagnosed FL in China (NCT03715309). One-hundred and fifteen patients were enrolled and treated with rituximab 375 mg/m2 intravenously on day 0 and lenalidomide 25 mg orally on day 1–10 for 6 cycles of induction treatment, as well as lenalidomide for 6 cycles and rituximab for 8 cycles of maintenance treatment. We found that inferior progression-free survival of the patients was significantly associated with elevated serum β2m and lymph node >6 cm, linking to decreased lymphoma cell autophagy and dendritic cell infiltration within the tumor microenvironment. PU.1 transcriptionally downregulated PD-L1 (Programmed death ligand 1) expression and upregulated 4-1BBL (4-1BB ligand) expression, increased lymphoma cell autophagy and dendritic cell maturation via PD-1/PD-L1 and 4-1BB/4-1BBL interaction. In vitro in co-culture system and in vivo in murine xenograft model, knockdown of PU.1 induced lenalidomide resistance, but sensitized FL cells to bi-specific PD-L1/4-1BB antibody or combined treatment of PD-L1 inhibitor and 4-1BB agonist. Collectively, PU.1 is essential in immunomodulatory effect of FL through PD-1/PD-L1- and 4-1BB/4-1BBL-mediated microenvironmental modulation. Dual targeting PD-L1 and 4-1BB could be an alternative immunotherapeutic strategy in the chemo-free era of FL treatment.

Interleukin-17A facilitates tumor progression via upregulating programmed death ligand-1 expression in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an inflammation-associated tumor with a dismal prognosis. Immunotherapy has become an important treatment strategy for HCC, as immunity is closely related to inflammation in the tumor microenvironment. Inflammation regulates the expression of programmed death ligand-1 (PD-L1) in the immunosuppressive tumor microenvironment and affects immunotherapy efficacy. Interleukin-17A (IL-17A) is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors. We hypothesized that IL-17A participates in tumor progression by affecting the level of immune checkpoint molecules in HCC. To investigate the effect and mechanism of action of IL-17A on PD-L1 expression and to identify attractive candidates for the treatment of HCC. The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR, western blotting, and flow cytometry. Mechanistic studies were conducted with gene knockout models and pathway inhibitors. The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells. The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro, and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo. IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner, whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A. IL-17A enhanced the survival of HCC cells in the coculture system. IL-17A increased the viability, G2/M ratio, and migration of HCC cells and decreased the apoptotic index. Cyclin D1, VEGF, MMP9, and Bcl-1 expression increased after IL-17A treatment, whereas BAX expression decreased. The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8 + T lymphocyte infiltration in an HCC mouse model. IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapentaplegic 2 signaling pathway in HCC cells. Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.

PLUNC downregulates the expression of PD-L1 by inhibiting the interaction of DDX17/β-catenin in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is characterized by high programmed death-ligand 1 (PD-L1) expression and abundant infiltration of non-malignant lymphocytes, which renders patients potentially suitable candidates for immune checkpoint blockade therapies. Palate, lung, and nasal epithelium clone (PLUNC) inhibit the growth of NPC cells and enhance cellular apoptosis and differentiation. Currently, the relationship between PLUNC (as a tumor-suppressor) and PD-L1 in NPC is unclear. We collected clinical samples of NPC to verify the relationship between PLUNC and PD-L1. PLUNC plasmid was transfected into NPC cells, and the variation of PD-L1 was verified by western blot and immunofluorescence. In NPC cells, we verified the relationship of PD-L1, activating transcription factor 3 (ATF3), and β-catenin by western blot and immunofluorescence. Later, we further verified that PLUNC regulates PD-L1 through β-catenin. Finally, the effect of PLUNC on β-catenin was verified by co-immunoprecipitation (Co-IP). We found that PLUNC expression was lower in NPC tissues than in paracancer tissues. PD-L1 expression was opposite to that of PLUNC. Western blot and immunofluorescence showed that β-catenin could upregulate ATF3 and PD-L1, while PLUNC could downregulate ATF3/PD-L1 by inhibiting the expression of β-catenin. PLUNC inhibits the entry of β-catenin into the nucleus. Co-IP experiments demonstrated that PLUNC inhibited the interaction of DEAD-box helicase 17 (DDX17) and β-catenin. PLUNC downregulates the expression of PD-L1 by inhibiting the interaction of DDX17/β-catenin in NPC.

An OMV-Based Nanovaccine as Antigen Presentation Signal Enhancer for Cancer Immunotherapy.

Antigen-presenting cells (APCs) process tumor vaccines and present tumor antigens as the first signals to T cells to activate anti-tumor immunity, which process requires the assistance of co-stimulatory second signals on APCs. The immune checkpoint programmed death ligand 1 (PD-L1) not only mediates the immune escape of tumor cells but also acts as a co-inhibitory second signal on APCs. The serious dysfunction of second signals due to the high expression of PD-L1 on APCs in the tumor body results in the inefficiency of tumor vaccines. To overcome this challenge, a previously established Plug-and-Display tumor vaccine platform based on bacterial outer membrane vesicles (OMVs) is developed into an "Antigen Presentation Signal Enhancer" (APSE) by surface-modifying PD-L1 antibodies (αPD-L1). While delivering tumor antigens, APSE can activate the expression of co-stimulatory second signals in APCs due to the high immunogenicity of OMVs. More importantly, the surface-modified αPD-L1 binds to the co-inhibitory signals PD-L1, potentially restoring CD80 function and ensuring efficient co-stimulatory second signals and activation of anti-tumor immunity. The results reveal the importance of PD-L1 blockage in the initiation process of anti-tumor immunity, and the second signal modulation capability of APSE can expand the application potential of cancer vaccines to less immunogenic malignancies.

Schisanhenol Inhibits the Proliferation of Hepatocellular Carcinoma Cells by Targeting Programmed Cell Death-ligand 1 via the STAT3 Pathways.

Programmed cell death-ligand 1 (PD-L1) is overexpressed in tumor cells, which promotes tumor cell survival and cell proliferation and causes tumor cells to escape T-cell killing. Schisanhenol, a biphenyl cyclooctene lignin-like compound, was extracted and isolated from the plant named Schisandra rubriflora (Franch.). In this work, we studied the anticancer potential of schisanhenol and explored whether schisanhenol mediated its effect by inhibiting the expression of PD-L1 in vitro and in vivo. In vitro, we performed western blot, immunofluorescence, immunoprecipitation, and colony formation assays to study the proteins, genes, and pathways related to the anti-tumour activity of schisanhenol. In vivo, we explored the antitumor activity of schisanhenol through orthotopic liver transplantation and subcutaneous transplantation tumor models of hepatocellular carcinoma (HCC) cells. We found that schisanhenol decreased the viability of HCC cells. It inhibited the expression of programmed cell death ligand-1 (PD-L1), which plays a pivotal role in tumorigenesis. Subsequently, schisanhenol suppressed the expression of PD-L1 by decreasing the activation of STAT3. Furthermore, we found that schisanhenol inhibited the activation of STAT3 via JAK/STAT3 (T705), Src/STAT3 (T705), and PI3K/AKT/mTOR/STAT3 (S727) pathways. Colony formation tests showed that schisanhenol suppressed cell proliferation by inhibiting PD-L1. Schisanhenol also enhanced cytotoxic T lymphocytes (CTL) activity and regained their ability to kill tumour cells in co-culture. Finally, in vivo observation confirmed the antitumor activity of schisanhenol. Schisanhenol inhibits the proliferation of HCC cells by targeting PD-L1 via the STAT3 pathways. These findings prove that schisanhenol is a valuable candidate for HCC therapeutics and reveal previously unknown characteristics of schisanhenol.

Cemiplimab in recurrent cervical cancer: Final analysis of overall survival in the phase III EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 trial.

Cemiplimab has demonstrated significantly longer survival than physician's choice of chemotherapy in patients with recurrent cervical cancer after first-line platinum-containing chemotherapy. We report the final survival analysis from the phase III randomized study (EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9). Cemiplimab (n=304) or chemotherapy (n=304) were administered every 3 weeks. The primary endpoint was overall survival (OS). Patients were included regardless of programmed cell death-ligand 1 (PD-L1) status. At a median follow-up of 47.3 months (data cut-off: April 20, 2023), median OS was 11.7 versus 8.5 months for patients treated with cemiplimab and chemotherapy, respectively (hazard ratio 0.67, 95% confidence interval 0.56-0.80, p<.00001). OS benefit was seen in PD-L1 positive and negative populations, even though more patients with PD-L1<1% (n=92), had poor performance status in the cemiplimab arm than the chemotherapy arm (61.4% vs 47.9%). This final analysis confirms that cemiplimab maintains survival benefit compared with chemotherapy in recurrent cervical cancer after progression on first-line platinum therapy, regardless of PD-L1 expression. The safety profile was consistent with published data; incidences of adverse events were similar between cemiplimab and chemotherapy groups. These results support the use of second-line cemiplimab for patients with recurrent cervical cancer.

Progress in understanding the regulatory mechanisms of immune checkpoint proteins PD-1 and PD-L1 expression.

Programmed Death Protein-1 (PD-1) is a cell surface receptor that serves as a checkpoint for T cells, playing a pivotal role in regulating T-cell apoptosis. The binding of PD-1 to its ligand, Programmed Death Ligand 1 (PD-L1), inhibits anti-tumor immunity by suppressing T-cell activation signals. Indeed, the PD-1/PD-L1 pathway governs the induction and maintenance of immune tolerance within the tumor microenvironment. Consequently, the regulation of PD-1/PD-L1 immune checkpoint expression is of paramount importance. This review summarizes the mechanisms governing PD1/PD-L1 expression at various stages, including transcription, post-transcription (mRNA processing), and post-translation (protein modifications), as well as immunotherapy targeting PD1/PD-L1, aiming to further explore novel strategies for tumor immunotherapy.

Cell-Penetrating Peptide Like Anti-Programmed Cell Death-Ligand 1 Peptide Conjugate-Based Self-Assembled Nanoparticles for Immunogenic Photodynamic Therapy.

The tumor-specific efficacy of the most current anticancer therapeutic agents, including antibody-drug conjugates (ADCs), oligonucleotides, and photosensitizers, is constrained by limitations such as poor cell penetration and low drug delivery. In this study, we addressed these challenges by developing, a positively charged, amphiphilic Chlorin e6 (Ce6)-conjugated, cell-penetrating anti-PD-L1 peptide nanomedicine (CPPD1) with enhanced cell and tissue permeability. The CPPD1 molecule, a bioconjugate of a hydrophobic photosensitizer and strongly positively charged programmed cell death-ligand 1 (PD-L1) binding cell-penetrating peptide (CPP), is capable of self-assembling into nanoparticles with an average size of 199 nm in aqueous solution without the need for any carriers. These carrier-free nanoparticles possess the ability to penetrate the cell membrane of cancer cells and target tumors expressing PD-L1 on their surface. Notably, CPPD1 nanoparticles effectively blocked programmed cell death-1 (PD-1)/PD-L1 interactions and reduced PD-L1 expression via lysosomal degradation. They also demonstrated the responsiveness of CPPD1 nanoparticles in photodynamic therapy (PDT) to a 635 nm laser, leading to the generation of ROS, and induction of various immunogenic cell deaths (ICD). Highly penetrating CPPD1 nanoparticles could immunogenically modulate the microenvironment of CT26 cancer and were also effective in treating abscopal metastatic tumors, addressing major limitations of traditional PDT.

Platinum drugs upregulate CXCR4 and PD-L1 expression via ROS-dependent pathways, with implications for novel combined treatment in gastric cancer.

CXC chemokine receptor 4 (CXCR4) and programmed cell death-ligand 1 (PD-L1) are two critical molecules involved in the tumor immune microenvironment. However, the impact of platinum drugs, such as cisplatin, on CXCR4 or PD-L1 expression and the underlying mechanisms in gastric cancer (GC) remain unknown. Moreover, the correlation between their expression levels in GC remains elusive. Immunohistochemistry, western blot, and RT-qPCR were performed to determine the expression pattern of CXCR4 and PD-L1 in GC. Clinical samples, patient-derived xenografts, and cell-derived xenografts were utilized to investigate the effects of platinum drugs on the expression levels of CXCR4 and PD-L1. Postchemotherapy resected GC tumor tissues showed higher CXCR4 and PD-L1 expression levels than pretreatment biopsies (p < 0.05). Similarly, GC xenografts treated with platinum-based chemotherapy exhibited increased CXCR4 and PD-L1 expression levels compared to saline-treated controls (p < 0.05). A positive correlation was detected between the expression levels of CXCR4 and PD-L1 in GC tumor tissues. Increased levels of CXCR4 and PD-L1 expression, in a dose- and time-dependent manner upon cisplatin treatment, were observed in GC cells (p < 0.05). Cisplatin-induced CXCR4 upregulation relies on ROS/HIF-1α and ROS/NF-κB pathways, while cisplatin-induced PD-L1 upregulation is cyclic GMP-AMP synthase/stimulator of IFN genes-dependent and associated with elevated ROS levels in GC cells. CXCR4 expression was found to be positively correlated with PD-L1 expression in GC. Platinum drugs upregulated the levels of CXCR4 and PD-L1 expression in GC. A combined strategy targeting CXCR-4 and PD-L1 might have clinical prospects for GC patients.