Programmed Death Receptor Ligand Research Articles

Clinical predictive value of PD-1/PD-L1-induced electrocardiogram changes for cardiotoxicity

Objective: To observe the electrocardiogram (ECG) changes of programmed death receptor 1 (PD-1)/programmed death receptor-ligand 1 (PD-L1) immune checkpoint inhibitors before and after immunotherapy of patients during clinical antitumor process, and to explore the occurrence and influencing factors of cardiotoxicity of immune checkpoint inhibitors. Methods: A total of 93 patients with locally advanced or metastatic solid tumors confirmed by pathological diagnosis in Cancer Hospital of Chinese Academy of Medical Sciences from October 1, 2019 to September 30, 2020 were selected and treated with PD-1/PD-L1 inhibitor monotherapy. Groups were divided according to immunotherapy regimen: Group A (drug code: 609A), 16 patients were given 1 mg/kg of the drug for 21 days; Group B (drug code: HX008), 23 patients were treated with 200mg for 21 days; Group C (drug code: GB226), 28 patients were treated with 3mg/kg for 14 days; Group D (drug code: LP002), 26 patients were treated with 900mg for 14 days. The patients were monitored and followed up for 10 cycles. The ECG results of each group were recorded, and the correlation between ECG abnormality and cardiotoxicity was analyzed. Results: A total of 75 patients showed abnormal ECG that met the diagnostic criteria. There was no significant difference in abnormal ECG rate after immunotherapy in group A (P＞0.05), while the incidence of adverse cardiac events increased after immunotherapy in group B (P＜0.05), and the abnormal ECG rate increased significantly after chemotherapy in group C and group D. There was statistical difference before and after immunotherapy (P＜0.001). The number of abnormal cases in group A (8 cases, 50.0%, 8/16) was significantly lower than that of group B (20 cases, 87.0%, 20/23). The number of abnormal cases in group C and group D was 24 (85.7%) and 23 (88.4%), respectively, without statistical difference (P＞0.05), but their abnormal rates of ECG were higher than that in group A. The incidence of electrical adverse events in immunotherapy center of patients with underlying diseases was 1.93 times higher than that of patients without underlying diseases. The incidence of central electrical adverse events during immunotherapy in group B, C and D was 6.667, 6.000 and 7.667 times higher than that in group A, respectively. Conclusions: The high sensitivity of early ECG changes induced by immune checkpoint inhibitors enables early prediction of related cardiotoxicity. The presence or absence of comorbid underlying disease and drug dosage are correlated with the occurrence of adverse cardiac events, and these early changes provide a evidence for clinical treatment and prevention.

Pulmonary Adenocarcinoma with Enteric Differentiation without TTF-1 Expression Is a Very Rare Subtype with Limited Treatment Options and Poor Prognosis

Plain Language SummaryPulmonary adenocarcinoma with enteric differentiation (PAED) without expression of thyroid transcription factor-1 (TTF-1) is an extremely rare and hard-to-treat variant of lung cancer. We collected clinicopathological data of 121 Caucasian patients with pulmonary adenocarcinoma without TTF-1 expression, their systemic therapy options, and the efficacy of their systemic treatment including 79 cases without a PAED and 42 cases with a PAED, compared these subgroups, and investigated patients’ response to chemotherapy and immunotherapy as first-line treatment. A comparison of clinicopathological data of TTF-1-negative PAED and non-PAED patients revealed a significantly lower frequency of high programmed death receptor ligand 1 (PD-L1) expression in PAED resulting in the lack of single-agent immunotherapy (p = 0.032) in this subgroup. Frequencies of an activating Kirsten rat sarcoma viral oncogene homolog (KRAS) gene mutation were high in both groups (46.7% and 50.0%), but a G12C gene mutation was seldomly noted (in 6.7% and 18.5% of patients with evaluable data). Median overall survival (OS) was poor in both groups (10 and 12 months). The majority of PAED patients received platinum-based and taxane-containing chemotherapy or chemo-/immunotherapy with an objective response rate of 31.6% and a disease control rate of 57.9%. Median progression-free survival (PFS) and OS of PAED patients with systemic therapy were very poor (3.9 months and 5.9 months). Caucasian patients with a TTF-1-negative PAED have a poor prognosis with reduced response rates to standard first-line systemic therapy and short survival times (PFS and OS).

Predictive Value of Lymphocyte-to-Neutrophil Ratio and Platelet-to-Neutrophil Ratio on PD-L1 Expression in Lung Cancer.

This study aimed to examine the predictive effect of the lymphocyte-to-neutrophil ratio (LNR) and the platelet-to-neutrophil ratio (PNR) on the expression of programmed death receptor ligand 1 (PD-L1) in patients diagnosed with lung cancer. The clinical records of 86 patients diagnosed with lung cancer between January 2020 and February 2022 at Fu Yang People's Hospital were retrospectively analyzed. The records included information on age, gender, smoking history, hematological indices at the time of admission, staging of the lung malignancy, histopathological subtype, comorbidities, and the expression levels of PD-L1. Patients were stratified into two distinct cohorts based on their PD-L1 expression levels: Those with an expression level greater than or equal to 1% were classified into the PD-L1 positive expression group, while the remainder were categorized as the PD-L1 negative expression group. Univariate analysis and multivariate logistic regression analysis were used to identify the influencing factors of PD-L1, and the diagnostic efficacy was calculated using the receiver operating characteristic (ROC) curve. Upon analysis, the PD-L1 positive expression group manifested notably lower values as compared to their counterparts in the PD-L1 negative expression group (LNR: 0.262 ± 0.105 vs. 0.390 ± 0.201; PNR: 41.03 [29.64, 50.11] vs. 49.50 [37.38, 73.83]), and these differences were statistically significant. There was a notable disparity in PD-L1 expression based on gender, with males exhibiting a statistically significant higher positivity rate compared to females. Furthermore, patients in Stages I-III of the disease demonstrated a markedly elevated PD-L1 positivity rate compared to those in Stage IV (p < 0.05). Incorporating univariates with statistical differences into multivariate logistic regression analysis suggests that stage and LNR are independent risk factors for PD-L1 negative expression. ROC curve analyses revealed that the area under the ROC curve (AUC) for LNR as an indicator for PD-L1 positive expression stood at 0.706, while the AUC for PNR was calculated at 0.687. PD-L1 expression is correlated with gender and lung cancer staging, and LNR and PNR have a predictive value for PD-L1 expression.

Circulating T cell status and molecular imaging may predict clinical benefit of neoadjuvant PD-1 blockade in oral cancer

BackgroundAddition of neoadjuvant immune checkpoint inhibition to standard-of-care interventions for locally advanced oral cancer could improve clinical outcome.MethodsIn this study, 16 evaluable patients with stage III/IV oral cancer were treated...

Self-Assembled PD-L1 Downregulator to Boost Photodynamic Activated Tumor Immunotherapy Through CDK5 Inhibition.

The immunosuppressive characteristics and acquired immune resistance can restrain the therapy-initiated anti-tumor immunity. In this work, an antibody free programmed death receptor ligand 1 (PD-L1) downregulator (designated as CeSe) is fabricated to boost photodynamic activated immunotherapy through cyclin-dependent kinase 5 (CDK5) inhibition. Among which, FDA approved photosensitizer of chlorin e6 (Ce6) and preclinical available CDK5 inhibitor of seliciclib (Se) are utilized to prepare the nanomedicine of CeSe through self-assembly technique without drug excipient. Nanoscale CeSe exhibits an increased stability and drug delivery efficiency, contributing to intracellular production of reactive oxygen species (ROS) for robust photodynamic therapy (PDT). The PDT of CeSe can not only suppress the primary tumor growth, but also induce the immunogenic cell death (ICD) to release tumor associated antigens. More importantly, the CDK5 inhibition by CeSe can downregulate PD-L1 to re-activate the systemic anti-tumor immunity by decreasing the tumor immune escape and therapy-induced acquired immune resistance. This work provides an antibody free strategy to activate systemic immune response for metastatic tumor treatment, which may accelerate the development of translational nanomedicine with sophisticated mechanism.

Application of Traditional Chinese Medicine in Inhibiting the PD-1/PD-L1 Pathway in the Treatment of Gastric and Colon Cancers

Immune checkpoint regulation is a negative feedback regulatory mechanism in the body, and sequential death receptor-1 (PD-1) and programmed death receptor ligand-1 (PD-L1) are known as immune checkpoints. The PD-1/PD-L1 pathway inhibits the activity of effector T cells through a negative regulatory mechanism to avoid excessive response-induced body damage. PD-L1 is highly expressed in many tumor tissues, and high PD-L1 expression can ultimately lead to tumor immune escape. Therefore, immune checkpoint blockade with inhibition of negative immune regulation therapy has become a cutting-edge hot spot for antitumor therapy, with the main target molecules being PD-1 and PD-L1. Recent years have seen promising progress in the study of traditional Chinese medicines and their effects on gastric and colon cancers, particularly in relation to the PD-1/PD-L1 pathway mechanisms. This review specifically examines the modulation of the PD-L1 pathway by certain traditional Chinese medicines in gastric and colon cancers, aiming to provide insights for the development of innovative drugs for these types of digestive cancers.

Enhancement of anti-PD-L1 antibody plus anlotinib efficacy due to downregulation of PD-L1 in the micro-conduit endothelium within the tumor: a randomized double-blind trial.

The possible enhancing effect of anlotinib on programmed death receptor ligand (PD-L1) antibody and the efficacy-predicting power of PD-L1 in micro-conduit endothelium, including lymphatic endothelial cells (LECs) and blood endothelial cells (BECs), were determined to identify patients who would benefit from this treatment. PD-L1 positivity in LECs, BECs, and tumor cells (TCs) was assessed using paraffin sections with multicolor immunofluorescence in an investigator's brochure clinical trial of TQB2450 (PD-L1 antibody) alone or in combination with anlotinib in patients with non-small cell lung cancer. Progression-free survival (PFS) with different levels of PD-L1 expression was compared between the two groups. Among 75 patients, the median PFS (mPFS) was longer in patients who received TQB2450 with anlotinib [10 and 12 mg (161 and 194 days, respectively)] than patients receiving TQB2450 alone (61 days) [hazard ratio (HR)10 mg = 0.390 (95% confidence interval {CI}, 0.201-0.756), P = 0.005; HR12 mg = 0.397 (0.208-0.756), P = 0.005]. The results were similar among 58 patients with high PD-L1 expression in LECs and TCs [159 and 209 vs. 82 days, HR10 mg = 0.445 (0.210-0.939), P = 0.034; HR12 mg = 0.369 (0.174-0.784), P = 0.009], and 53 patients with high PD-L1 expression in BECs and TCs [161 and 209 vs. 41 days, HR10 mg = 0.340 (0.156-0.742), P = 0.007; HR12 mg = 0.340 (0.159-0.727), P = 0.005]. No differences were detected in the mPFS between the TQB2450 and combination therapy groups in 13 low/no LEC-expressing and 18 low/no BEC-expressing PD-L1 cases. Mono-immunotherapy is not effective in patients with high PD-L1 expression in LECs and/or BECs. Anlotinib may increase efficacy by downregulating PD-L1 expression in LECs and/or BECs, which is presumed to be a feasible marker for screening the optimal immune patient population undergoing anti-angiogenic therapy.

Sharks give a handle to potent anti-tumor multiparatopic antibodies inducing membrane depletion of PD-L1

Despite the immense clinical success of the antibody therapeutics that neutralize programmed death receptor ligand 1 (PD-L1) and thus resurrect Tcell antitumor activity, the patient response rates remain low. In this issue of Cell Chemical Biology, Ludwig etal.1 reveal novel topologies of multiparatopic antibodies that mediate potent PD-L1 downregulation.

Preclinical development of novel PD-L1 tracers and first-in-human study of [68Ga]Ga-NOTA-RW102 in patients with lung cancers

BackgroundThe programmed cell death protein-1 (PD-1)/programmed death receptor ligand 1 (PD-L1) axis critically facilitates cancer cells’ immune evasion. Antibody therapeutics targeting the PD-1/PD-L1 axis have shown remarkable efficacy in various...

OMA1 competitively binds to HSPA9 to promote mitophagy and activate the cGAS–STING pathway to mediate GBM immune escape

BackgroundImmunotherapy with checkpoint inhibitors, especially those targeting programmed death receptor 1 (PD-1)/PD-1 ligand (PD-L1), is increasingly recognized as a highly promising therapeutic modality for malignancies. Nevertheless, the efficiency of immune...

Frequency of Programmed Death Receptor Ligand 1 Expression and Clinicopathological Factors Associated With Metastatic Triple-Negative Breast Cancer at a Tertiary Cancer Care Centre in South India.

Purpose Triple-negative breast cancer (TNBC) has a poor outcome compared to other subtypes. Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm in metastatic diseases as well as in neoadjuvant setting. The response to these agents is affected by programmed death ligand 1 (PDL1) receptor expression which are reported objectively as a score. PDL1 is a prognostic marker also. Here, we present clinicopathological characteristics of metastatic TNBCs, report the proportion of PDL1 expression and its association with clinicopathological factors as well as survival. Methods This is a prospective study carried out at a tertiary cancer care centre in South India. Case records of all breast cancer patients treated in two years between August 2021 and July 2023 were reviewed, patients with metastatic TNBC were selected. Patient's characteristics, histological features, molecular profile, and treatment were analyzed. PDL1 testing was carried out on pretreatment tumor tissue sections with immunohistochemistry (IHC) (Dako 22C3). PDL1 staining was interpreted as negative or positive based on combined positive score (CPS), with an expression less than 10 considered negative. Results A total of 118 patients were analyzed. With a median age of 46 years (36-65 years), 52.5% (62/118) were premenopausal. Family history of Ca Breast was seen in 22% (26/118) patients. A majority of patients had left-sided tumor 55.9% (66/118). Visceral metastasis was more common 96.6% (82/118) than skeletal. Radical intent of treatment was adopted in 10% as patients had oligometastatic disease at presentation. As front-line treatment, anthracycline-based chemotherapy was administered to the majority 54.2% (64/118). The PDL1 expression with CPS more or equal to 10 was seen in 32.2% (38/118) patients. Survival was associated with menopausal status (p value=0.000) and family history (p value=0.028) but notwith PDL1 nor sidedness in our study. Estimated survival at 12 months in PDL1 negative case is 10 ± 0.29 months, while in PDL1 positive case it is slightly more at 10± 0.75 months, but difference was not found to be statistically significant (p value=0.15). Conclusion TNBCs are highly aggressive subtype with limited treatment options and poorer outcomes. Our study shows PDL1 expression in 31.66% of the cases similar to other literature from India. Survival is associated with menopausal status and family history. No association was found between survival and PDL1 as well sidedness in our study.

Effectiveness of Second-Line Cabozantinib in Metastatic Clear Cell Renal Cell Carcinoma Patients After First-Line Treatment with Immune Checkpoint Inhibitor-based Combinations.

Cabozantinib, a tyrosine kinase inhibitor (TKI), is a prevalent second-line (2 L) therapy and was approved for use after progression on TKIs. However, the 1 L treatment setting has changed since the approval of cabozantinib monotherapy in salvage therapy settings. To assess the differential effectiveness of cabozantinib after prior progression on 1 L ipilimumab with nivolumab (IPI + NIVO) compared to programmed death receptor-1 (PD-1) or PD-1 ligand (PD-L1) inhibitors (PD1/L1i) with TKIs. Utilizing a nationwide electronic health record (EHR)-derived de-identified database, we included patients with metastatic clear cell renal cell carcinoma (mccRCC) who received 1 L treatment with an immune checkpoint inhibitor (ICI)-based combination and 2 L treatment with cabozantinib monotherapy. These patients were categorized based on the type of 1 L ICI-based combination received: IPI + NIVO vs. PD1/L1i with TKI. Real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS) were summarized using Kaplan-Meier curves and compared using Cox-proportional hazard models adjusted for International mRCC Database Consortium (IMDC) risk groups. Among 12,285 patients with metastatic renal cell carcinoma, 237 were eligible and included. Median rwTTNT was 8 months for the IPI + NIVO subgroup and 7.5 months for the PD1/L1i + TKI subgroup (HR 1.05, 95% CI: 0.74-1.49, p = 0.8). Median rwOS was 17 months for IPI + NIVO and 16 months for PD1/L1i + TKI subgroup (HR 0.79, 95% CI: 0.52-1.20, p = 0.3). Cabozantinib remains effective as a 2 L therapy for mccRCC independent of the type of prior 1 L ICI-based combination. Further research is needed to validate these findings and explore the ideal sequencing of therapies.

Primary squamous cell carcinoma of the parotid salivary gland: a clinical observation

Introduction. Malignant tumors of the salivary glands account for 3–5 % of all cases of head and neck cancer. Squamous cell carcinoma is the rarest histological variant of this pathology. It accounts for an average of 1.6 %. Among large salivary gland tumors, squamous cell carcinoma most often occurs in the parotid salivary gland.Aim. To present a clinical case of primary disseminated cancer of the parotid salivary gland with squamous cell structure.Clinical observation. A 70-year-old patient was under observation who was diagnosed with a primary squamous cell tumor of the parotid salivary gland with multiple metastases during a complex examination. He was sick for about 6 months when asymmetry of left half of the face appeared due to a painful neoplasm in the parotid salivary gland. Recently, the patient has noted increased tumor growth. Objective examination revealed peripheral paralysis of the facial nerve on the left. In the parotid-masticatory region on the left, with a transition to the zygomatic region, there is a dense painful immobile exophytic tumor with infiltration into soft tissues of the face and skin 6.5 × 5.0 cm in size with an ulcer in the center. Laterally, it reaches the tragus, and at the bottom-the angle of the lower jaw. In the submandibular region on the left, metastatic lymph nodes 2.5 × 2.0 cm in size are palpated. A biopsy was collected. Histological conclusion: non-keratinizing squamous cell carcinoma. Expression of the programmed death receptor ligand (PD-L1) in the tumor is negative. Mutations of genes Her2-neu and BRAF were not detected. According to medical imaging methods, multiple metastases were found in the lungs, liver, zygomatic bone and tumor growth in the maxillary sinus on the left. The diagnosis was established: cancer of the parotid salivary gland, stage IVC, cT4N1M1, with metastases to the liver, lungs and bones. Polychemotherapy was prescribed according to the scheme: 5-fluorouracil + cisplatin + cetuximab + bisphosphonates. After 3 cycles, a partial regression is obtained.Conclusion. The primary squamous cell carcinoma is prone to an aggressive course and has an unfavorable prognosis, especially in patients over 60 years of age with skin and facial nerve damage, as well as the presence of regional and distant metastases. Differential diagnosis is necessary to exclude the secondary nature of the tumor. The presented case is a rare example of primary squamous cell carcinoma of the parotid salivary gland with extensive metastatic lesion and regression of the pathological process after polychemotherapy in combination with targeted therapy.

Prognostic significance of tumor microenvironment assessed by machine learning algorithm in surgically resected non-small cell lung cancer.

A methodology to assess the immune microenvironment (IME) of non-small cell lung cancer (NSCLC) has not been established, and the prognostic impact of IME factors is not yet clear. This study aimed to assess the IME factors and evaluate their prognostic values. We assessed CD8+ tumor-infiltrating lymphocyte (TIL) density, forkhead box protein P3+ (Foxp3+ ) TIL density, and programmed death receptor ligand-1 (PD-L1) tumor proportion score (TPS) using a machine-learning algorithm in whole-slide imaging (WSI). We dichotomized patients according to TIL density or TPS and compared their clinical outcomes. Between September 2014 and September 2015, 165 patients with NSCLC were enrolled in the study. We assessed IME factors in the epithelium, stroma, and their combination. An improvement in disease-free survival (DFS) was observed in the high CD8+ TIL density group in the epithelium, stroma, and the combination of both. Moreover, the group with high PD-L1 TPS in the epithelium showed better DFS than that with low PD-L1 TPS. In the multivariate analysis, the CD8+ TIL density in the combination of epithelium and stroma and PD-L1 TPS in the epithelium were independent prognostic factors (hazard ratio [HR] = 0.43; 95% confidence interval [CI] = 0.26-0.72; p = .001, HR = 0.49; 95% CI = 0.30-0.81; p = .005, respectively). Our approach demonstrated that the IME factors are related to survival in patients with NSCLC. The quantitative assessment of IME factors enables to discriminate patients with high risk of recurrence, who can be the candidates for adjuvant therapy. Assessing the CD8+ TIL density in the combination of epithelium and stroma might be more useful than their individual assessment because it is a simple and time-saving analysis of TILs in WSI.

A Crosstalk Between Castration-Resistant Prostate Cancer Cells, M2 Macrophages, and NK Cells: Role of the ATM-PI3K/AKT-PD-L1 Pathway

ABSTRACT Castration-resistant prostate cancer (CRPC) in males is associated with a poor prognosis and a higher risk of treatment-related adverse effects, with high mortality among cancers globally. It is thus imperative to explore novel potential molecules with dual therapeutic and biomarker functions. Based on the recent research findings, the expression levels of ataxia telangiectasia mutant kinase (ATM) in prostate cancer (PC) tissues collected from CRPC patients were higher than hormone-dependent PC patients. Using CRPC cell lines (C4–2 and CWR22Rv1), the transwell chamber experiments revealed ATM promoted macrophage recruitment in CRPC cells in vitro via C-X-C motif chemokine ligand 12 (CXCL12). Further in vitro investigations demonstrated that polarized macrophages prevented NK cell recruitment and reduced the immunocidal activity of NK cells against CRPC cell lines. Moreover, ATM boosted programmed death receptor ligand 1 (PD-L1) expression while inhibiting NK group 2D (NKG2D) ligand expression in selected cell lines via PI3K/AKT signaling pathway. The in vivo investigations revealed ATM induced proliferation of CRPC and macrophage recruitment, while the NK cell recruitment was found to suppress ATM expression and CRPC proliferation. In conclusion, it could be demonstrated that inhibiting ATM increased the susceptibility of CRPC to NK cell inhibitors by dampening the CXCL12 and PI3K/AKT-PD-L1 pathways, thereby offering a novel and individualized treatment protocol for treating CRPC.

MicroRNA-326 negatively regulates CD155 expression in lung adenocarcinoma.

Treatment with immune checkpoint inhibitors induces a durable response in some patients with non-small-cell lung cancer, but eventually gives rise to drug resistance. Upregulation of CD155 expression is implicated as one mechanism of resistance to programmed death receptor-1 (PD-1)/PD-1 ligand (PD-L1) inhibitors, and it is therefore important to characterize the mechanisms underlying regulation of CD155 expression in tumor cells. The aim of this study was to identify microRNAs (miRNAs) that might regulate CD155 expression at the posttranscriptional level in lung cancer. Comprehensive miRNA screening with target prediction programs and a dual-luciferase reporter assay identified miR-346, miR-328-3p, miR-326, and miR-330-5p as miRNAs that bind to the 3'-UTR of CD155 mRNA. Forced expression of these miRNAs suppressed CD155 expression in lung cancer cell lines. Immunohistochemical staining of CD155 in tissue specimens from 57 patients with lung adenocarcinoma revealed the median tumor proportion score for CD155 to be 68%. The abundance of miR-326 in these specimens with a low level of CD155 expression was significantly greater than in specimens with a high level (p < 0.005). Our results thus suggest that miR-326 negatively regulates CD155 expression in lung adenocarcinoma and might therefore play a role in the development of resistance to PD-1/PD-L1 inhibitors.

Effects of Tolerant Nanoparticles Loaded with Various Regulatory Molecules on the Development of Experimental Autoimmune Encephalomyelitis

This research investigated the effects of tolerating nanoparticles (tNPs) loaded with multiple regulatory molecules on progression of experimental autoimmune encephalomyelitis (EAE). The polylactic acid-glycolic acid copolymer (PLGA), multiple regulatory molecular fragments (Fc) (programmed death receptor ligand 1-Fc (PD-L1-Fc), CD47-Fc), transforming growth factor (TGF-β1), and multiple oligodendrocyte glycoprotein (MOG) antigen peptides (p-MOG) were selected to prepare the tNPs (MRM-tNPs) loaded with various regulatory molecules. Then, the MRM-tNPs were applied in MOG35-55 polypeptide-induced EAE mouse model. According to the treatment methods, the mice were rolled into a group A (BS therapeutic agent), a group B (no-load-NPs), a group C (MOG-tNPs), and a group D (MRM-tNPs). The therapeutic effects were evaluated by the inflammatory infiltration degree (IID), demyelination loss degree (DLD), and apoptosis rate (AR) of CD4+ and CD8+ T cells. The Results showed that the encapsulation rate (ER) of TGF-β1 was 87.65%, and its cumulative release rate (RR) was 58.22%. There were obvious fluorescence signals on MRM-tNPs, MRM-tNPs without PD-L1, and MRM-tNPs without CD47. The neurological function (NF) score in the group D after MRM-tNPs treatment was less than 2 points (P &lt;0.05). The scores of IID and DLD in the brain and spinal cord (SC) of EAE mice in the group D were much lower to those in groups A, B, and C, and the ARs of CD4+ and CD8+ T cells were higher (P &lt;0.05). In conclusion, the tNPs loaded with various regulatory molecules can promote the apoptosis of antigen-specific T cells (AST) and reduce the infiltration and demyelination of inflammatory cells, thus alleviating the EAE.

The Combination of PD-L1 and CTLA-4 Suppression Significantly Decreased the Expression Levels of Cancer Stem Cell Factors in the Pancreatic Cancer Cell Line

Background: It is thought that a limited number of aberrant cancer stem cells (CSCs), which encourage carcinogenesis, tumor metastasis, and treatment resistance, are the cause of pancreatic cancer, a disease with a high mortality rate. Increasing evidence shows that CSCs use immunosuppressive properties to avoid immune system identification. In Pancreatic cancer, the therapeutic consequences of the relationship between the expression of immune checkpoints such as programmed death receptor ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the presence of CSCs are poorly known. As a result, in the present investigation, we examined how the expression levels of CSCs were affected by PD-L1 and CTLA-4 knockdown using specific siRNA. Methods: Independently and together, PD-L1 and CTLA-4 siRNA were transfected into MIA PaCa-2 cells. RNA extraction and cDNA synthesis were then performed. Finally, using qRT-PCR, the gene expression levels of CSCs markers, including Nanog, CD133, CD44, and Oct-4, in transfected groups were measured. Results: In the MIA PaCa-2 cell line, siRNA-mediated inhibition of PD-L1 and CTLA-4 decreased the expression of CSC factors. Moreover, combined suppression of these two stemness-related immune checkpoints significantly decreased Nanog, CD133, CD44, and Oct-4 expression compared to inhibition of PD-L1 and CTLA-4 separately. Conclusion: Considering that the combination of PD-L1 and CTLA-4 suppression using siRNA significantly decreased the expression levels of CSCs factors, this approach may be regarded as an effective therapy for this cancer.

Real-World Biomarker Test Utilization and Subsequent Treatment in Patients with Early-Stage Non-small Cell Lung Cancer in the United States, 2011-2021.

Biomarker testing is increasingly crucial for patients with early-stage non-small cell lung cancer (eNSCLC). We explored biomarker test utilization and subsequent treatment in eNSCLC patients in the real-world setting. Using COTA's oncology database, this retrospective observational study included adult patients ≥ 18years old diagnosed with eNSCLC (disease stage 0-IIIA) between January 1, 2011 and December 31, 2021. Date of first eNSCLC diagnosis was the study index date. We reported testing rates by index year for patients who received any biomarker test within 6months of eNSCLC diagnosis and by each molecular marker. We also evaluated treatments received among patients receiving the five most common biomarker tests. Among the 1031 eNSCLC patients included in the analysis, 764 (74.1%) received ≥ 1 biomarker test within 6months of eNSCLC diagnosis. Overall, epidermal growth factor receptor (EGFR; 64%), anaplastic lymphoma kinase (ALK; 60%), programmed death receptor ligand 1 (PD-L1; 48%), ROS proto-oncogene 1 (ROS1; 46%), B-Raf proto-oncogene (40%), mesenchymal epithelial transition factor receptor (35%), Kirsten rat sarcoma viral oncogene (29%), RET proto-oncogene (22%), human epidermal growth factor receptor 2 (21%), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (20%) were the 10 most frequently tested biomarkers. The proportion of patients undergoing biomarker testing rose from 55.3% in 2011 to 88.1% in 2021. The most common testing methods were Sanger sequencing for EGFR (244, 37%), FISH (fluorescence in situ hybridization) for ALK (464, 75%) and ROS1 (357, 76%), immunohistochemical assay for PD-L1 (450, 90%), and next-generation sequencing testing for other biomarkers. Almost all the 763 patients who received the five most common biomarker tests had a test before the initiation of a systemic treatment. This study suggests a high biomarker testing rate among patients with eNSCLC in the US, with testing rates for various biomarkers increasing over the past decade, indicating a continuous trend towards the personalization of treatment decisions.

Nano-Liposome Co-Loaded with C-X-C Chemokine Ligand 12/CXCR4 Pathway Inhibitor Synergistically Increases the Immune Efficacy of Anti-PD-L1 and Increase Anti-Tumor Activity of Effector T Cells

Blockade of the immune checkpoint programmed cell death receptor-1 (PD-1) or programmed death receptor ligand-1 (PD-L1) enhances the antitumor activity of effector T cells. However, many patients lack response to PD-1/PD-L1 therapy. Enhancing the efficacy of immune checkpoint inhibitors by improving the immunosuppressive tumor microenvironment (TME) has emerged as a promising cancer treatment strategy. In this study, a new nano-liposome (PD-L1/siCXCL12-Lp) of C-X-C chemokine ligand 12 (CXCL12) siRNA and anti-PD-L1 peptide (PD-L1/siCXCL12-Lp) responsive to matrix metalloproteinases (MMPs) was constructed, combined with siCXCL12. The regulation of TME and the immunomodulatory effect of anti-PD-L1 peptide to synergistically enhance the antitumor immune response. The animal experiment protocol was reviewed and approved by the Biomedical Ethics Committee of Peking University. This study showed that PD-L1/siCXCL12-Lp directly downregulated CXCL12 expression in vitro (33.8%) and in vivo (15.5%), and effectively increased the CD8+/Treg ratio (20.0%), which favored anti-PD-L1 peptides better exert its immune function. Combination therapy significantly inhibited tumor growth (52.08%) with good safety, exploring new ideas for cancer immunotherapy.