Programmed Death Ligand Research Articles

Mechanism of the KIAA1429/KLF1/PD-L1 Axis in Regulating Immune Escape in Non-small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC), accounting for approximately 80% of lung cancer cases, remains the leading cause of cancer-related mortality. Immune evasion is a critical challenge in NSCLC, contributing to poor treatment outcomes. This study investigates the role of KIAA1429 in immune evasion, aiming to identify novel therapeutic targets and provide a theoretical basis for NSCLC treatment. NSCLC cell lines were cultured to assess the expression of KIAA1429, KLF transcription factor (KLF1), and programmed cell death ligand 1 (PD-L1). Co-culture experiments were conducted with peripheral blood mononuclear cells (PBMCs) to evaluate cytotoxicity, CD8+T cell proportions, and levels of interferon-gamma (IFN-γ)/interleukin (IL)-10/IL-2. Additionally, N6-methyladenosine (m6A) modification in NSCLC cells, m6A enrichment on KLF1, and KLF1 mRNA stability were analyzed. Results showed increased expression of KIAA1429 and KLF1 in NSCLC cells. Knockdown of KIAA1429 inhibited NSCLC cell proliferation, enhanced PBMC cytotoxicity and CD8+T cell activation, increased IFN-γ and IL-2 levels, and decreased IL-10 levels. Mechanistically, KIAA1429 stabilized KLF1 mRNA level through m6A modification, promoting both KLF1 and PD-L1 expression. Overexpression of KLF1 or PD-L1 reversed the immune-modulating effects of KIAA1429 knockdown. In conclusion, KIAA1429 facilitates immune evasion in NSCLC by stabilizing KLF1 mRNA and upregulating PD-L1 expression.

Network Medicine-Based Strategy Identifies Maprotiline as a Repurposable Drug by Inhibiting PD-L1 Expression via Targeting SPOP in Cancer.

Immune checkpoint inhibitors (ICIs) are drugs that inhibit immune checkpoint (ICP) molecules to restore the antitumor activity of immune cells and eliminate tumor cells. Due to the limitations and certain side effects of current ICIs, such as programmed death protein-1, programmed cell death-ligand 1, and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) antibodies, there is an urgent need to find new drugs with ICP inhibitory effects. In this study, a network-based computational framework called multi-network algorithm-driven drug repositioning targeting ICP (Mnet-DRI) is developed to accurately repurpose novel ICIs from ≈3000 Food and Drug Administration-approved or investigational drugs. By applying Mnet-DRI to PD-L1, maprotiline (MAP), an antidepressant drug is repurposed, as a potential PD-L1 modifier for colorectal and lung cancers. Experimental validation revealed that MAP reduced PD-L1 expression by targeting E3 ubiquitin ligase speckle-type zinc finger structural protein (SPOP), and the combination of MAP and anti-CTLA4 in vivo significantly enhanced the antitumor effect, providing a new alternative for the clinical treatment of colorectal and lung cancer.

Synthesis of a Pd2L4 Hydrazone Molecular Cage Through Multiple Reaction Pathways

Molecular cages are preorganized molecules with a central cavity, typically formed through the reaction of their building blocks through chemical bonds. This requires, in most cases, forming and breaking reversible bonds during the cage formation reaction pathway for error correction to drive the reaction to the cage product. In this work, we focus on both Pd–ligand and hydrazone bonds implemented in the structure of a Pd2L4 hydrazone molecular cage. As the cage contains two different types of reversible bonds, we envisaged a cage formation comparative study by performing the synthesis of the cage through three different reaction pathways involving the formation of Pd–ligand bonds, hydrazone bonds, or a combination of both. The three reaction pathways produce the cage with yields ranging from 73% to 79%. Despite the complexity of the reaction, the cage is formed in a high yield, even for the reaction pathway that involves the formation of 16 bonds. This research paves the way for more sophisticated cage designs through complex reaction pathways.

Ni‐MOF Engineered System Targeting Macrophage Aurora A Kinase for Bone Loss Prevention Through PD‐L1 Activation

AbstractPostmenopausal bone loss due to estrogen deficiency necessitates effective therapeutic strategies. Our study explores targeting macrophage Aurora A kinase to mitigate bone loss. Aurora A kinase phosphorylation is observed being increased in bone marrow‐derived macrophages (BMDMs) from ovariectomy (OVX) mice, along with a reduction in programmed death‐ligand 1 (PD‐L1) expression. Detailed analysis reveals that PD‐L1 plays an immunomodulatory role by lowering the ratio of T helper 17 cells and regulatory T cells. The metabolic shift toward glycolysis through transcriptome sequencing, induced by Aurora A kinase inhibition, is essential for PD‐L1 expression in BMDMs. The interaction between Aurora A kinase and cytochrome C oxidase subunit 5B is found to enhance PD‐L1 expression. To apply these findings therapeutically, a multifunctional system is developed using a Nickel‐metal organic framework combined with bisphosphonate and MLN8237 (BP@Ni‐MOF/MLN8237). This system targets bone tissues through bisphosphonate and effectively delivers MLN8237 to macrophages, promoting PD‐L1 expression for a favorable immune environment. Moreover, this system exhibits an obvious angiogenic effect. The present study highlights the crucial roles of macrophage Aurora A kinase and PD‐L1 in maintaining bone homeostasis as well as the angiogenesis effect by Ni‐MOF engineered system, presenting a promising therapeutic approach to prevent postmenopausal bone loss.

Unveiling the Immune effects of AHR in tumors: a decade of insights from bibliometric analysis (2010–2023)

BackgroundThe Aryl Hydrocarbon Receptor (AHR) is a transcription factor that regulates several biological processes. Its potential in anti-tumor immunotherapy is becoming clearer, yet no bibliometric studies on this topic exist. This study aims to understand the current research landscape and identify future directions through a bibliometric analysis of AHR’s anti-tumor immunological effects.Methods We conducted a comprehensive bibliometric analysis of AHR antitumor immunotherapy papers in the Web of Science Core Collection. Various aspects of the publications were analyzed, and research hotspots and future trends were identified using scientific bibliometric tools and statistical methods.ResultsWe collected 592 English papers published between 2010 and 2023, with an almost annual increase. Most publications were from the USA, followed by China, Germany, and Italy. The journal “Frontiers in Immunology” had the most papers, and the most cited paper was Christiane A. Opitz’s “An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor.” The research is centered around AHR gene expression, with a growing focus on intestinal disease and the development of Programmed cell death ligand 1 (PD-L1) drugs.ConclusionThis bibliometric study highlights the significance of AHR in immunomodulatory research, outlining the research trends and key contributors. It suggests AHR’s immune effects may mediate the process of colitis cancer transformation, providing valuable insights for future anti-tumor immunotherapy strategies based on AHR.

Malignant Salivary Gland Neoplasm of the Tongue Base with EWSR1::BEND2 Fusion: An Unusual Case with Literature Review.

Salivary gland malignancies may have overlapping architectural patterns, tumor morphology, and immunohistochemical phenotypes, presenting challenges in precise classification. Molecular phenotyping has become quite useful for providing an additional diagnostic modality, and potential drug targets. Here we reported a young female patient with salivary gland tumor of the tongue base harboring genetic alterations by next generation sequencing (NGS). The morphological, immunohistochemical and molecular features of this case were described, and related literature was reviewed. The tumor showed an epithelial myoepithelial architecture arranged in cords and tubules interwoven with a chondromyxoid stroma, along with perineural invasion and adjacent striated muscle infiltration. Myoepithelial cells were positive for CK5/6, partially positive for P63 and CK7, and sporadically positive for S100. Immunoprofiling revealed a low density of infiltrating lymphocytes and macrophages and the absence of programmed death ligand 1 (PD-L1). Notably, RNA-based NGS showed EWSR1::BEND2 gene fusion in this tumor, and EWSR1 break-apart was confirmed by fluorescence in situ hybridization. This led to a final diagnosis of a minor salivary gland malignancy with EWSR1::BEND2 fusion. Only two other cases of salivary gland tumors with EWSR1::BEND2 fusion had been previously reported, which were also detected via RNA-based NGS. This study emphasized that EWSR1::BEND2 fusion may drive the carcinogenesis in salivary glands neoplasia. In clinic RNA-based NGS could be essential for precise genotyping of EWSR1 fusion in this rare disease.

Total baseline tumor size predicts survival among patients with advanced small-cell lung cancer receiving chemotherapy plus programmed death-ligand 1 inhibitor as first-line therapy: a multicenter retrospective observational study

IntroductionTotal baseline tumor size (BTS) is a prognostic factor for programmed death 1 and programmed death-ligand 1 (PD-L1) inhibitor treatments. However, the prognostic value of total BTS for patients with small-cell lung cancer (SCLC) who receive chemotherapy plus PD-L1 inhibitor remains unknown. Thus, in this study, we aimed to determine whether total BTS is associated with prognosis in patients with SCLC who receive chemotherapy plus PD-L1 inhibitor as first-line therapy.MethodsThis study included patients with extensive-stage SCLC or post-chemoradiotherapy recurrence of limited-stage SCLC who received chemotherapy plus PD-L1 inhibitor as first-line therapy from August 2019 to December 2022. The two lesions with the largest diameter among the measurable lesions in each organ were selected from up to five organs (maximum of 10 lesions), and the sum of all diameters was defined as total BTS. The patients were divided into two groups, large or small, with total BTS using X-tile software. Median survival was analyzed using the Kaplan–Meier method, and the groups were compared using the log-rank test. Univariate and multivariate analyses examined the association between total BTS and prognosis.ResultsFifty patients were included; 14% had large total BTS (>183.2 mm) and 86% had small total BTS (≤183.2 mm). The median observation period was 10.5 months. The large total BTS group showed significantly worse overall survival than the small total BTS group (median: 26.8 months vs. 5.7 months, P = 0.0003). The multivariate analysis indicated that large total BTS was an independent negative predictor of overall survival (hazard ratio: 7.14, 95% confidence interval: 1.89–26.96).DiscussionTotal BTS is a potentially useful prognostic factor for patients with advanced SCLC who receive chemotherapy plus PD-L1 inhibitor as first-line therapy.

Camrelizumab combined with gemcitabine and apatinib in treating advanced PD-L1-positive biliary tract cancers.

The efficacy of combined chemotherapy and immunotherapy has previously been demonstrated in patients with biliary tract cancer. The aim of this study was to assess the efficacy and safety of camrelizumab in combination with gemcitabine and apatinib as a first- or second-line treatment for advanced programmed death-ligand 1 (PD-L1)-positive biliary tract cancer. This prospective, single-arm, and exploratory clinical trial aimed at recruiting 20 PD-L1-positive patients (tumor proportion score ≥1% or combined positive score ≥1) who met the inclusion criteria. Camrelizumab (200 mg) was administered in combination with gemcitabine (800 mg/m2) and apatinib (250 mg). The primary endpoint was the objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Fourteen patients were enrolled between September 2, 2020, and December 15, 2022. At the data cutoff on August 16, 2023, the median follow-up time was 11.4 months (interquartile range, 4.5-15.4), with one patient still undergoing treatment. Among the enrolled patients, six achieved a partial response, and four had stable disease. The ORR was 42.9% (95% confidence interval [CI], 17.7-71.1), and the DCR was 71.4% (95% CI, 41.9-91.6). The median PFS was 5.4 months (95% CI, 2.8-not reached), and the median OS was 13.5 months (95% CI, 5.7-not reached). The most frequent grade 3 or 4 treatment-related adverse event was neutropenia (n = 4, 29%). The combination of camrelizumab, gemcitabine, and apatinib showed promising efficacy and acceptable safety in patients with advanced PD-L1-positive biliary tract cancer.

The prognostic implications of podoplanin in cancer-associated fibroblasts and PD-L1 expression in high-grade neuroendocrine carcinoma of the lung.

Podoplanin (PDPN) expression in cancer-associated fibroblasts (CAFs) (CAF-PDPN) is considered a poor prognostic factor in nonsmall cell lung cancer, but little is known about its clinical significance in high-grade neuroendocrine carcinoma of the lung (HGNEC). This study examines the association between CAF-PDPN and stromal programmed death-ligand 1 (PD-L1) expression and the prognostic implications of CAF-PDPN and PD-L1 expression status in surgically resected HGNEC patients. Immunohistochemical analyses were performed on 121 resected HGNEC specimens using antibodies against PDPN and PD-L1. Correlations between CAF-PDPN, stromal PD-L1 expression, and clinicopathologic features and their implications for survival were analyzed statistically. There were substantially more large-cell neuroendocrine carcinomas in the stromal PD-L1-positive group and more vascular invasion in the tumoral PD-L1-positive group. PDPN expression in CAF was moderately correlated with stromal PD-L1 expression (ρ = 0.567, p < 0.001). In a survival analysis combining CAF-PDPN and stromal PD-L1 status, the 5-year RFS rates for Group A: CAF-PDPN (+)/stromal PD-L1 (+), Group B: CAF-PDPN (+)/stromal PD-L1 (-), Group C: CAF-PDPN (-)/stromal PD-L1 (+), and Group D: CAF-PDPN (-)/stromal PD-L1 (-) were 62.0%, 46.8%, 17.5%, and 20.2%, respectively, with corresponding 5-year OS rates of 76.6%, 69.2%, 27.0%, and 25.3%. The log-rank test showed statistically significant differences among the groups in RFS (p < 0.001) and OS (p < 0.001). There is a correlation between CAF-PDPN and tumoral/stromal PD-L1 expression, and positive status for either CAF-PDPN or stromal PD-L1 expression could be an independent favorable prognostic factor in surgically resected HGNEC patients.

The role of PD-1/PD-L1 pathway in ulcerative colitis and changes following tonsil-derived mesenchymal stem cells treatment

Background/Aims: The programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has not been fully evaluated in inflammatory bowel disease. We evaluated PD-1/PD-L1 levels in patients with ulcerative colitis (UC) and their significance in tonsil-derived mesenchymal stem cells (TMSCs) treatment.Methods: Using acute and chronic murine colitis model, we measured the PD-1 and PD-L1 levels in inflamed colonic tissues pre- and post-treatment with TMSCs. We also measured PD-1 and PD-L1 levels in colonic tissues from UC patients, compared to normal controls.Results: In the analysis using human colonic tissues, a significant increase in the levels of PD-1 and PD-L1 was observed in the colonic mucosa of patients with UC compared with normal controls (&lt;i&gt;p&lt;/i&gt; &lt; 0.001 and &lt;i&gt;p&lt;/i&gt; = 0.005, respectively). When comparing the maximal disease extent, PD-L1 levels were highest in patients with proctitis (38.5 ± 46.7), followed by left-side colitis (17.5 ± 23.1) and extensive colitis (5.2 ± 8.2) (&lt;i&gt;p&lt;/i&gt; &lt; 0.001). In the chronic colitis model, the level of PD-L1 was decreased (&lt;i&gt;p&lt;/i&gt; = 0.040) and the level of PD-1 increased more than in normal controls (&lt;i&gt;p&lt;/i&gt; = 0.047). After treatment with TMSC, significant improvements were observed in body weight, disease activity index, and colon length recovery. Additionally, the levels of PD-1 and PD-L1 were recovered; PD-L1 significantly increased (&lt;i&gt;p&lt;/i&gt; = 0.031), while the level of PD-1 decreased (&lt;i&gt;p&lt;/i&gt; = 0.310).Conclusions: The altered expression of PD-1 and PD-L1 in colonic mucosa may be a possible mechanism of UC, and T-MSC-derived PD-L1 could help suppress colitis.

Leveraging chemotherapy-induced PD-L1 upregulation to potentiate targeted PD-L1 degradation using nanoparticle-based targeting chimeras

The combination of nab-paclitaxel and the programmed death-ligand 1(PD-L1) antibody atezolizumab showed limited benefits in clinical trials involving PD-L1-positive triple-negative breast cancer patients. This observed lack of success is attributed to the upregulation of PD-L1 on tumor cells induced by paclitaxel, leading to resistance against PD-L1 antibodies. Here, we introduce nanoparticle-based PD-L1 targeting chimeras (NanoTACPD-L1) to induce PD-L1 degradation instead of blockade. NanoTACPD-L1 initiates endocytosis independent of specific lysosome-targeting receptors, and delivers membrane-bound PD-L1 to lysosomes for targeted degradation. Furthermore, the efficiency of degradation is directly correlated with the PD-L1 expression level. NanoTACPD-L1 effectively leverages paclitaxel-induced PD-L1 upregulation to enhance PD-L1 degradation, employing a “Meet-Plot-With-Plot” strategy. In a series of in vivo models, NanoTACPD-L1 demonstrates superior therapeutic efficacy and immune activation, both when administered individually and in combination with paclitaxel, surpassing the effects of anti-PD-L1 antibody treatment. Collectively, our study provides a nanotechnology-based tool that can be enhanced by paclitaxel for PD-L1 degradation and validates its potential application in overcoming chemo-immunotherapy resistance.

Invasive Stratified Mucin-producing Carcinoma of the Uterine Cervix: Comparison of Its Clinicopathological Characteristics and Programmed Death-ligand 1 Expression Status With Those of Other Endocervical Adenocarcinomas.

Invasive stratified mucin-producing carcinoma (ISMC) is a rare but aggressive variant of endocervical adenocarcinoma (EAC). The aim of this study was to investigate the differences in clinicopathological features, patient outcomes, and programmed death-ligand 1 (PD-L1) expression among ISMC, usual-type EAC (UEA), and gastric-type EAC (GEA). PD-L1 22C3 immunostaining was performed using 20 ISMCs, 20 UEAs, and 20 GEAs. Combined positive score (CPS) method was used to assess PD-L1 immunoreactivity. ISMC was diagnosed at a younger age and showed a more advanced stage and shorter survival than UEA. The disease-free survival (DFS) and overall survival (OS) rates of ISMC patients were lower than those of UEA but comparable to those of GEA. ISMC type was an independent prognostic factor for predicting short DFS [hazard ratio (HR)=2.790, 95% confidence interval (CI)=1.153-6.756] and OS (HR=6.071, 95%CI=1.257-29.327). All ISMCs showed PD-L1 over-expression with a mean CPS of 44.5 (range=10-100), which was higher than those of UEA (mean CPS=8.2) and GEA (mean CPS=6.5). PD-L1 positivity (CPS≥1) was also an independent prognostic factor for worse OS (HR=2.472, 95%CI=1.097-5.570). Despite PD-L1 over-expression, ISMC patients treated with pembrolizumab showed no clinical response. All examined ISMCs over-expressed PD-L1. ISMC showed higher PD-L1 expression than UEA and GEA and worse survival than UEA. PD-L1 over-expression was found to be a significant predictor for worse DFS and OS in patients with ISMC. Our data suggest that PD-L1 over-expression is associated with poor ISMC prognosis.

NCAPD3 is a prognostic biomarker and is correlated with immune infiltrates in glioma.

Non-SMC Condensin II Complex Subunit D3 (NCAPD3) has been linked with the genesis and progression of multiple human cancers. Nevertheless, the scientific value and molecular process of NCAPD3 in glioma remain unclear. We explored the level of NCAPD3 expression in pan-cancer by multiple online databases. And we focused on the level and prognostic value of NCAPD3 expression in glioma by immunohistochemistry (IHC) and survival analysis. Meanwhile, we verified the relationship between NCAPD3, biological function and immune infiltration in glioma by Linkedomics and SangerBox databases. The expression of NCAPD3 was increased in a variety of cancers, including glioma. Its high expression was strongly related to WHO grade (P=0.002) and programmed cell death ligand 1 (PD-L1) expression of glioma (P=0.001). Patients with a high level of NCAPD3 expression had a lower overall survival (OS) in glioma than patients with a low level of NCAPD3 expression. Multivariate statistical analyses showed NCAPD3 expression (P=0.040), WHO grade (P<0.001), 1p/19q codeletion (P<0.001), recurrence (P<0.001), age (P=0.023), and chemotherapy status (P=0.001) were meaningful independent prognostic factors in patients with glioma. Furthermore, bioinformatics analysis proved that NCAPD3 has been linked to immune infiltration in glioma. High level of NCAPD3 expression may serve as a promising prognostic biomarker and correlate with dendritic cell infiltration, representing a potential immunotherapy target in glioma.

Spatial RNA sequencing supports programmed death ligand 2 (PD-L2) as a potential immunotherapy target in high-grade serous ovarian carcinoma

Spatial RNA sequencing supports programmed death ligand 2 (PD-L2) as a potential immunotherapy target in high-grade serous ovarian carcinoma

The influence of biophysical niche on tumor-associated macrophages in liver cancer.

HCC, the most common type of primary liver cancer, is a leading cause of cancer-related mortality worldwide. Although the advancement of immunotherapies by immune checkpoint inhibitors (ICIs) that target programmed cell death 1 or programmed cell death 1-ligand 1 has revolutionized the treatment for HCC, the majority is still not beneficial. Accumulating evidence has pointed out that the potent immunosuppressive tumor microenvironment in HCC poses a great challenge to ICI therapeutic efficacy. As a key component in tumor microenvironment, tumor-associated macrophages (TAMs) play vital roles in HCC development, progression, and ICI low responsiveness. Mechanistically, TAM can promote cancer invasion and metastasis, angiogenesis, epithelial-mesenchymal transition, maintenance of stemness, and most importantly, immunosuppression. Targeting TAMs, therefore, represents an opportunity to enhance the ICI therapeutic efficacy in patients with HCC. While previous research has primarily focused on biochemical cues influencing macrophages, emerging evidence highlights the critical role of biophysical signals, such as substrate stiffness, topography, and external forces. In this review, we summarize the influence of biophysical characteristics within the tumor microenvironment that regulate the phenotype and function of TAMs in HCC pathogenesis and progression. We also explore the possible mechanisms and discuss the potential of manipulating biophysical cues in regulating TAM for HCC therapy. By gaining a deeper understanding of how macrophages sense and respond to mechanical forces, we may potentially usher in a path toward a curative approach for combinatory cancer immunotherapies.

Inhibition of Notch enhances efficacy of immune checkpoint blockade in triple-negative breast cancer.

Aberrant Notch, which is a defining feature of triple-negative breast cancer (TNBC) cells, regulates intercellular communication in the tumor immune microenvironment (TIME). This includes tumor-associated macrophage (TAM) recruitment through Notch-dependent cytokine secretion, contributing to an immunosuppressive TIME. Despite the low response rate of TNBC to immune checkpoint blockade (ICB), here, we report that inhibition of Notch-driven cytokine-mediated programs reduces TAMs and induces responsiveness to sequentially delivered ICB. This is characterized by the emergence of GrB+ cytotoxic T lymphocytes (CTLs) in the primary tumor. A more impressive effect of sequential treatment is observed in the lung where TAM depletion and increased CTLs are accompanied by near-complete abolition of metastases. This is due to (i) therapeutic reduction in Notch-dependent, prometastatic circulating factors released by the primary tumor, and (ii) elevated PD ligand 1 (PD-L1) in lung metastases, rendering them profoundly sensitive to ICB. These findings highlight the potential of combination cytokine inhibition and ICB as an immunotherapeutic strategy in TNBC.

Comprehensive Advanced Physicochemical Characterization and In Vitro Human Cell Culture Assessment of BMS-202: A Novel Inhibitor of Programmed Cell Death Ligand

Background/Objectives: BMS-202, is a potent small molecule with demonstrated antitumor activity. The study aimed to comprehensively characterize the physical and chemical properties of BMS-202 and evaluate its suitability for topical formulation, focusing on uniformity, stability and safety profiles. Methods: A range of analytical techniques were employed to characterize BMS-202. Scanning Electron Microscopy (SEM) was used to assess morphology, Differential Scanning Calorimetry (DSC) provided insights of thermal behavior, and Hot-Stage Microscopy (HSM) corroborated these thermal behaviors. Molecular fingerprinting was conducted using Raman spectroscopy and Fourier Transform Infrared (FTIR) spectroscopy, with chemical uniformity of the batch further validated by mapping through FTIR and Raman microscopies. The residual water content was measured using Karl Fisher Coulometric titration, and vapor sorption isotherms examined moisture uptake across varying relative humidity levels. In vitro safety assessments involved testing with skin epithelial cell lines, such as HaCaT and NHEK, and Transepithelial Electrical Resistance (TEER) to evaluate barrier integrity. Results: SEM revealed a distinctive needle-like morphology, while DSC indicated a sharp melting point at 110.90 ± 0.54 ℃ with a high enthalpy of 84.41 ± 0.38 J/g. HSM confirmed the crystalline-to-amorphous transition at the melting point. Raman and FTIR spectroscopy, alongside chemical imaging, confirmed chemical uniformity as well as validated the batch consistency. A residual water content of 2.76 ± 1.37 % (w/w) and minimal moisture uptake across relative humidity levels demonstrated its low hygroscopicity and suitability for topical formulations. Cytotoxicity testing showed dose-dependent reduction in skin epithelial cell viability at high concentrations (100 µM and 500 µM), with lower doses (0.1 µM to 10 µM) demonstrating acceptable safety. TEER studies indicated that BMS-202 does not disrupt the HaCaT cell barrier function. Conclusions: The findings from this study establish that BMS-202 has promising physicochemical and in vitro characteristics at therapeutic concentrations for topical applications, providing a foundation for future formulation development focused on skin-related cancers or localized immune modulation.

Simple Analysis Using Immunohistochemical Staining for Tumor-Infiltrating Lymphocytes in Brain Metastasis of Small Cell Lung Cancer

Background: We investigated the distribution of tumor-infiltrating lymphocytes (TILs) and the expression of programmed cell death-ligand 1 (PD-L1) in patients with brain metastasis (BM) from small cell lung cancer (SCLC). Methods: A retrospective analysis was performed on 12 surgical specimens of BMs from SCLC at our institute for 5 years. The Immunofluorescence-based Tissue Microenvironment Analysis Panel (MAP) was utilized for the detection of TILs, including CD3, CD8, PD-1, and PD-L1, in pathological archival specimens of BMs. The correlation between the overall survival (OS) and the above-mentioned markers was analyzed in the patients.Results: Positive rates of CD3+ TILs in the tumor parenchyma versus tumor stroma were 0.60±0.94% versus 1.76±2.72% (p=0.010), respectively; positive rates of CD8+ TILs in the tumor parenchyma versus tumor stroma were 0.80±0.78% versus 2.46±3.72% (p=0.016), respectively. There was no co-expression of CD8+ and PD-1+ TILs in the tumor parenchyma of 11 cases, and the infiltration density of co-expressed CD3+ and PD-1+ TILs was more than 10/mm2 in only 1 case. There was no co-expression 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 BMs, and 3 cases (25%) were positive. Survival analysis showed that patients with positive CD3+ TILs had significantly longer OS (p=0.040). Conclusions: The distribution of TILs in BM of SCLC is low and mainly distributed in the stroma, with the low expression of PD-L1 in the tumor tissues.

Avelumab reduces STAT3 expression with effects on IL-17RA and CD15.

Avelumab is a human antibody that targets the programmed cell death ligand-1 (PD-L1) protein in cancer cells. Novel anticancer therapies for renal cell carcinoma (RCC) consider cluster of differentiation 15 (CD15) and interleukin 17 receptor A (IL-17RA) as potential targets. Notably, the expression of PD-L1, CD15 and IL-17RA is dependent on signal transducer and activator of transcription 3 (STAT3). The aim of the study was to investigate whether targeting PD-L1 with avelumab alters the expression levels of CD15 and IL-17RA, and to assess the STAT3-mediated regulation of CD15 and IL-17RA. We applied immunocytochemistry (ICC) and confocal laser scanning (CLS) microscopy to assess the expression and localization of the immunotherapy targets in 3 renal cancer cell lines and 1 healthy renal cell line. After treatment with 20 ng/mL avelumab, renal cancer cells showed a reduction in STAT3 expression. The expression of CD15 increased in cancer cells that exhibited a high level of IL-17RA, and the membrane signal of CD15 was reduced. In other renal cancer cell lines, the expression of CD15 decreased. Conversely, the level of IL-17RA changed only in healthy renal cells after treatment with avelumab, with no impact on renal cancer cells. Our study suggests that the targeting of PD-L1 with avelumab alters the expression of CD15 and IL-17RA, which play an important prognostic and therapeutic role in novel anticancer therapy.

Programmed Cell Death-Ligand 1 Expression and Clinical Outcomes Among Patients with Resected, Early-Stage Non-Small Cell Lung Cancer: A Real-World Study

Treatment options for non-small cell lung cancer (NSCLC) are evolving, given recent and expected approvals of immune checkpoint inhibitors (ICIs) targeting programmed cell death-(ligand) 1 (PD-1/PD-L1). We retrospectively evaluated outcomes among patients with resected stage IB-IIIA NSCLC tumors expressing PD-L1 using PALEOS (Pan-cAnadian Lung cancEr Observational Study) data (2016–2019). Key outcomes included PD-L1 expression rate and treatment patterns, recurrence, and median overall (mOS) and disease-free survival (mDFS) among PD-L1+ patients. Among 539 PD-L1–tested patients, 317 (58.8%) were PD-L1+ (≥1%). At diagnosis, 35.3%, 39.8%, and 24.9% of PD-L1+ patients had stage IB, II, or IIIA disease. Forty-one percent had received adjuvant therapy. At 22.6 months (median follow-up), first disease recurrence had occurred in 31.9% of patients, primarily at metastatic sites. After first metastatic recurrence, ICI regimens were the most common first systemic therapy (29.8%). mOS was not reached; mDFS was 40.0 months. At four years, DFS probability was 44%. Four-year OS and DFS rates were generally similar when stratified by PD-L1 expression (1–49% vs. ≥50%). These findings underscore the generally poor outcomes experienced by patients with early-stage, resected, PD-L1+ NSCLC after treatment with available adjuvant therapies, and provide context to recent and emerging trials of new treatment options.