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The risk of treatment‐related toxicities with programmed cell death 1 and its ligand (PD‐1/PD‐L1) inhibitors in patients with lung cancer is unclear and inconclusive. PubMed, EMBASE, and the Cochrane Library databases were systematically searched without language restrictions from inception to May 31, 2024 to identify Phase 3 randomized controlled trials of lung cancer comparing PD‐1/PD‐L1 inhibitors versus placebo/best supportive care (alone or in combination with nontargeted chemotherapy) that had available data regarding treatment‐related adverse events (TRAEs) or incidence and sample size. Random‐effect models were employed to study the pooled relative risk (RR) and 95% confidence intervals (CIs). Finally, 36 trials, involving 19,693 participants, fulfilled the inclusion criteria. PD‐1/PD‐L1 inhibitors significantly augmented the likelihood of developing all‐grade (RR, 1.03; 95% CI, 1.01–1.04, p <.01) and grade ≥3 TRAEs (RR, 1.16; 95% CI, 1.10 to 1.23, p <.01). PD‐1/PD‐L1 inhibitors substantially augmented the odds of developing treatment‐related serious adverse events (SAEs) (RR, 1.48; 95% CI, 1.27–1.71, p <.01) and fatal adverse events (FAEs) (RR, 1.42; 95% CI, 1.11–1.82, p <.01). Subgroup analyses indicated that the RR of SAEs and FAEs were generally consistent, regardless of treatment type, tumor type, treatment setting, PD‐1/PD‐L1 inhibitors type and study design. The most common causes of FAEs were respiratory failure/insufficiency (33.3%), cardiac events (16.1%), and hematological disorders (10.1%). We demonstrated that PD‐1/PD‐L1 inhibitors were significantly correlated with higher possibility of developing treatment‐related toxicities, especially SAEs and FAEs, compared with placebo/best supportive care controls. [ABSTRACT FROM AUTHOR]

Background: Programmed cell death 1 (PD-1) is a cell surface protein that serves as an immune checkpoint in conjunction with its two ligands, PD-L1 and PD-L2. Recently, there has been a lot of interest in the role of the PD-1/PD-L1 pathway in immunoregulation. Objective: To assess both PD-1 and PD-L1 levels in vitiligo patients' marginal and nonlesional biopsies compared with normal controls and to correlate them with disease parameters. Patients and methods: A total of 30 vitiliginous patients and 30 age and sex-matched controls were included. Full history and clinical examination were done and ELISA measured tissue levels of PD-1 and PD-L1 from lesional and nonlesional biopsies. Results: Levels of tissue PD-1 in marginal biopsies (mean 7.89±2.48 ng/mg) were significantly higher than in nonlesional biopsies (mean 3.65±1.11 ng/mg; P <0.001) and significantly higher than the control PD-l level (mean 1.47±0.499 ng/mg; P <0.001). Nonlesional PD-1 level was also significantly higher than the control PD-l level (P <0.001). A statistically significant positive correlation was found between marginal and nonlesional PD-1 levels; (rho=0.792, P <0.001). Levels of tissue PD-L1 in marginal biopsies (mean 115±7.86 pg/mg) were significantly lower than in nonlesional skin (mean 194±8.12 pg/mg; P <0.001), and significantly lower than in controls (mean 283±27.8 pg/mg; P <0.001). Nonlesional PD-L1 level was also significantly lower than the control PD-Ll level (P <0.001). Conclusion: Our results suggest that the PD-1/PD-L1 checkpoint seems to be implicated in the loss of peripheral tolerance in human vitiligo, with PD-1 being highly expressed, yet insufficiently stimulated due to lack of local PD-L1 expression. Since PD1 plays an important role, its agonists may have therapeutic implications in vitiligo and other autoimmune diseases but need wider-scale studies before clinical implementation. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) alone or in combination with standard chemotherapy for advanced urothelial carcinoma (UC) have been tested as first-line treatment in clinical trials. This study aimed to evaluate the clinical outcomes of programmed cell death 1 (PD-1) inhibitor alone or combined with chemotherapy for patients with locally advanced or metastatic UC in a real world clinical care setting, and sought to identify prognostic factors for overall survival (OS). Methods: A retrospective, real-world study involving 35 locally advanced or metastatic UC patients treated with PD-1 inhibitor alone or in combination with chemotherapy was conducted. Kaplan–Meier curves were used to assess progression-free survival (PFS) and OS. A Cox regression analysis was conducted to explore the association of baseline variables with OS. Results: In our cohort of 35 patients, 7 patients were treated with PD-1 inhibitor alone and 28 with PD-1 inhibitor plus platinum-based chemotherapy. The median OS was 16.0 months (95% CI: 11.9–20.1), and median PFS was 12.0 months (95% CI: 8.6–15.4) for all patients. PD-1 inhibitor combined with chemotherapy was associated with better PFS than PD-1 inhibitor monotherapy (HR: 0.19, p = 0.018). Treatment-related adverse events (AEs) of any grade occurred in 5 (71.4%) patients who received PD-1 inhibitor and 24 (85.7%) patients who received PD-1 inhibitor plus chemotherapy. Eastern Cooperative Oncology Group (ECOG) performance status (PS) and neutrophil-lymphocyte ratio (NLR) were identified as prognostic factors. Conclusion: This study suggested that patients with locally advanced or metastatic UC could benefit from PD-1 inhibitor alone or combined with chemotherapy in daily clinical practice. ECOG PS and NLR can be used for prognostication of survival. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions This study aimed to determine the clinical relevance of the influence of coadministration of immune checkpoint inhibitors (ICIs) on the analgesic effects of opioids, focusing on the amount of change in opioid dosage.This study used data from patients who used opioids during anticancer therapy at the Oita University Hospital between September 2014 and October 2023. The primary outcome measure was the amount of change in morphine mg equivalent opioid dose during the period of anticancer therapy. Propensity score matching was performed to reduce confounding effects.The study enrolled 235 patients; 101 received ICI and 134 received no ICI. Before propensity score matching, there were significant differences between the ICI and non‐ICI groups in lines of anticancer therapy, type of primary cancer, body mass index, maximum opioid dose and the amount of change in opioid dose. Following propensity score matching, 73 patients each were included in the ICI and non‐ICI groups. Analysis of the propensity score‐matched cohort showed a significant increase in the median amount of change in opioid dose in ICI group vs non‐ICI group (22.5 vs. 15.0 morphine mg equivalents, interquartile range; 0.0, 40.0 vs. 0.0, 30.0, P = .044). Multiple regression analysis identified ICI administration and body mass index as significant independent factors associated with the amount of change in opioid dose (P = .014 and .027, respectively).ICI administration significantly increased opioid dosage regardless of patient background. Our findings would provide valuable insight into future pain management strategies. [ABSTRACT FROM AUTHOR]

Background Programmed cell death 1 (PD-1) is a cell surface protein that serves as an immune checkpoint in conjunction with its two ligands, PD-L1 and PD-L2. Recently, there has been a lot of interest in the role of the PD-1/PD-L1 pathway in immunoregulation. Objective To assess both PD-1 and PD-L1 levels in vitiligo patients’ marginal and nonlesional biopsies compared with normal controls and to correlate them with disease parameters. Patients and methods A total of 30 vitiliginous patients and 30 age and sex-matched controls were included. Full history and clinical examination were done and ELISA measured tissue levels of PD-1 and PD-L1 from lesional and nonlesional biopsies. Results Levels of tissue PD-1 in marginal biopsies (mean 7.89±2.48 ng/mg) were significantly higher than in nonlesional biopsies (mean 3.65±1.11 ng/mg; P

Abstract Background Immune checkpoint inhibitors (ICIs) alone or in combination with standard chemotherapy for advanced urothelial carcinoma (UC) have been tested as first-line treatment in clinical trials. This study aimed to evaluate the clinical outcomes of programmed cell death 1 (PD-1) inhibitor alone or combined with chemotherapy for patients with locally advanced or metastatic UC in a real world clinical care setting, and sought to identify prognostic factors for overall survival (OS). Methods A retrospective, real-world study involving 35 locally advanced or metastatic UC patients treated with PD-1 inhibitor alone or in combination with chemotherapy was conducted. Kaplan–Meier curves were used to assess progression-free survival (PFS) and OS. A Cox regression analysis was conducted to explore the association of baseline variables with OS. Results In our cohort of 35 patients, 7 patients were treated with PD-1 inhibitor alone and 28 with PD-1 inhibitor plus platinum-based chemotherapy. The median OS was 16.0 months (95% CI: 11.9–20.1), and median PFS was 12.0 months (95% CI: 8.6–15.4) for all patients. PD-1 inhibitor combined with chemotherapy was associated with better PFS than PD-1 inhibitor monotherapy (HR: 0.19, p = 0.018). Treatment-related adverse events (AEs) of any grade occurred in 5 (71.4%) patients who received PD-1 inhibitor and 24 (85.7%) patients who received PD-1 inhibitor plus chemotherapy. Eastern Cooperative Oncology Group (ECOG) performance status (PS) and neutrophil-lymphocyte ratio (NLR) were identified as prognostic factors. Conclusion This study suggested that patients with locally advanced or metastatic UC could benefit from PD-1 inhibitor alone or combined with chemotherapy in daily clinical practice. ECOG PS and NLR can be used for prognostication of survival.

Introduction: Iparomlimab (QL1604) is a humanized immunoglobulin G4 mAb against programmed cell death protein 1 (PD-1). Here, we report the preliminary efficacy, safety, pharmacokinetics, and immunogenicity of iparomlimab in patients with advanced solid tumors. Methods: In this open-label, phase 1c study, patients with advanced or metastatic solid tumors, either failed or had no standard therapies available, were enrolled and received intravenous iparomlimab at 3 mg/kg once every 3 weeks. The primary efficacy endpoint was the objective response rate (ORR) assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: Between July 20, 2020, and September 6, 2021, 71 patients were enrolled and received at least one dose of iparomlimab. The ORR was 9.9% (7/71) and disease control rate was 36.6% (26/71). Median duration of response of all responders was 10.7 months [95% confidence interval (CI), 1.4-not estimable]. Additionally, the median time to progression, progression-free survival, and overall survival were 1.4 months (95% CI, 1.4–2.8), 1.4 months (95% CI, 1.4–2.7), and 9.7 months (95% CI, 7.2–15.3), respectively. A total of 52 (73.2%) patients experienced treatment-related adverse events (TRAEs) (grade ≥ 3, 19.7%). The most common TRAE (≥ 10%) was anemia (18.3%). A total of 20 (28.2%) experienced immune-related adverse events (grade ≥ 3, 7.0%). TRAEs leading to discontinuation of study drug occurred in 4 (5.6%) patients, including immune-mediated myocarditis (2 patients), Guillain–Barré syndrome (1 patient), and diarrhea (1 patient). Conclusions: Iparomlimab showed preliminary clinical activity and had a manageable safety profile in patients with advanced solid tumors. These results support further investigation of iparomlimab as monotherapy or in combination therapy in advanced solid tumors. Trial Registration: ClinicalTrials.gov identifier, NCT05801094. Retrospectively registered in 2023–03–24. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is frequent, an imbalance between helper cells (Th) and regulatory T cells (Treg) is the fundamental immunological cause of RA. This study investigates how recombinant human programmed cell death 1 (PD-L1) protein affects circulating T follicular helper (cTfh), circulating T follicular regulatory (cTfr), and their equilibrium. Magnetic bead sorting was used to select CD4+CXCR5+T cells from RA patients' and healthy individuals' peripheral blood mononuclear cells for in vitro growth. Recombinant human PD-L1 protein stimulated CD4+CXCR5+T cells. Cell counting kit 8 (CCK-8), flow cytometry surface labeling, ELISA, and RT-PCR were used to measure CD4+CXCR5+T cell proliferation inhibition, cTfh and cTfr frequencies, IL-21 expression, and PI3K, AKT, Bcl-6, and Blimp-1 mRNA levels. The recombinant human PD-L1 protein dose-dependently inhibited the proliferation of CD4+CXCR5+T cells in active RA peripheral blood. However, it has a weaker inhibitory effect on healthy peripheral blood CD4+CXCR5+T cells. PD-L1 protein decreased cTfh in active RA peripheral blood CD4+CXCR5+T overall cultured cells but did not affect cTfr; The cTfr/cTfh ratio increased but did not affect the frequency of cTfh and cTfr in healthy persons' cultured CD4+CXCR5+T cells. PD-L1 protein reduced IL-21 in CD4+CXCR5+T cell culture supernatant from active RA peripheral blood. Recombinant human PD-L1 protein lowered PI3K, AKT, and Bcl- 6 mRNA in active RA peripheral blood CD4+CXCR5+T cell culture, including significant differences. But Blinmp-1 mRNA variations were neither substantial nor statistically different. PD-1/PD-L1 limits cTfh proliferation, differentiation, and activation via the PI3K/AKT signaling pathway regulates its immunological balance with cTfr, and corrects the cTfr/cTfh imbalance by controlling their interaction. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC), the most common primary liver malignancy and the sixth most common cancer globally, remains fatal for many patients with inappropriate responses to treatment. Recent advancements in immunotherapy have transformed the treatment landscape for advanced HCC. However, variability in patient responses to immunotherapy highlights the need for biomarkers that can predict treatment outcomes. This manuscript comprehensively reviews the evolving role of biomarkers in immunotherapy efficacy, spanning from blood-derived indicators—alpha-fetoprotein, inflammatory markers, cytokines, circulating tumor cells, and their DNA—to tissue-derived indicators—programmed cell death ligand 1 expression, tumor mutational burden, microsatellite instability, and tumor-infiltrating lymphocytes. The current body of evidence suggests that these biomarkers hold promise for improving patient selection and predicting immunotherapy outcomes. Each biomarker offers unique insights into disease biology and the immune landscape of HCC, potentially enhancing the precision of treatment strategies. However, challenges such as methodological variability, high costs, inconsistent findings, and the need for large-scale validation in well-powered two-arm trial studies persist, making them currently unsuitable for integration into standard care. Addressing these challenges through standardized techniques and implementation of further studies will be critical for the future incorporation of these biomarkers into clinical practice for advanced HCC. [ABSTRACT FROM AUTHOR]

PurposeThyroid eye disease (TED) primarily occurs in hyperthyroid patients, sometimes resulting in poor visual prognosis. Although other autoimmune diseases have been reported to be associated with serum programmed cell death 1 (PD-1), the relationship with TED remains unknown. This study investigated the relationship between TED and immune checkpoint molecules.MethodsSerum immune checkpoint molecules were measured in TED and control patient blood samples. In TED patients, blood samples were compared before and 6 months after steroid pulse treatment. Cytometry analysis was additionally performed in TED and control patients to compare the expression of (PD-1) of T cells.ResultsSerum concentrations of PD-1 in TED and control patients were 163.49 ± 79.01 (pg/mL) and 123.58 ± 46.61 (pg/mL) (P = 0.03). Serum PD-L1 concentration in TED was 157.89 ± 55.34 (pg/mL), while 152.58 ± 22.70 (pg/mL) in control patients (P = 0.92). For flow cytometry analysis, the mean fluorescence intensity (MFI) ratio of PD-1 in Foxp3high CD45RA- of the CD4+ T cells and CD127-CD25high of the CD4+ T cells were higher in TED versus control patients (P = 0.04, P = 0.02). There was also a higher percentage of PD-1 expressions on CD4+ T cells and Foxp3high CD45- T cells in TED patients versus that for control patients (P < 0.001, P = 0.003).ConclusionsPD-1 expression of CD4+Foxp3+ regulatory T cells appear to be associated with TED pathogenesis before and after treatment. Regulatory T cells expressed PD-1 have possibilities of clinical activity and autoimmune pathology of TED.

Objective: This study evaluated the safety and efficacy of an anti-epidermal growth factor receptor (EGFR) antibody (SCT200) and an anti-programmed cell death 1 (PD-1) antibody (SCT-I10A) as third-line or subsequent therapies in patients with rat sarcoma viral oncogene (RAS)/v-raf murine sarcoma viral oncogene homolog B (BRAF) wild-type (wt) metastatic colorectal cancer (mCRC). Methods: We conducted a multicenter, open-label, phase Ib clinical trial. Patients with histologically confirmed RAS/BRAF wt mCRC with more than two lines of treatment were enrolled and treated with SCT-I10A and SCT200. The primary endpoints were the objective response rate (ORR) and safety. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: Twenty-one patients were enrolled in the study through January 28, 2023. The ORR was 28.57% and the DCR was 85.71% (18/21). The median PFS and OS were 4.14 and 12.84 months, respectively. The treatment-related adverse events (TRAEs) were tolerable. Moreover, compared with the monotherapy cohort from our previous phase I study evaluating SCT200 for RAS/BRAF wt mCRC in a third-line setting, no significant improvements in PFS and OS were observed in the combination group. Conclusions: SCT200 combined with SCT-I10A demonstrated promising efficacy in previously treated RAS/BRAF wt mCRC patients with an acceptable safety profile. Further head-to-head studies with larger sample sizes are needed to validate whether the efficacy and safety of combined anti-EGFR and anti-PD-1 therapy are superior to anti-EGFR monotherapy in the third-line setting. (Registration No. NCT04229537).

Objective: Immunotherapy targeting programmed cell death 1 (PDCD1 or PD-1) and its ligands has shown remarkable promise and the regulation mechanism of PD-1 expression has received arising attention in recent years. PDCD1 exon 3 encodes the transmembrane domain and the deletion of exon 3 produces a soluble protein isoform of PD-1 (sPD-1), which can enhance immune response by competing with full-length PD-1 protein (flPD-1 or surface PD-1) on T cell surface. However, the mechanism of PDCD1 exon 3 skipping is unclear. Methods: The online SpliceAid program and minigene expression system were used to analyze potential splicing factors involved in the splicing event of PDCD1 exon 3. The potential binding motifs of heterogeneous nuclear ribonucleoprotein K (HNRNPK) on exon 3 predicted by SpliceAid were mutated by site-directed mutagenesis technology, which were further verified by pulldown assay. Antisense oligonucleotides (ASOs) targeting the exonic splicing silencer (ESS) on PDCD1 exon 3 were synthesized and screened to suppress the skipping of exon 3. The alternative splicing of PDCD1 exon 3 was analyzed by semiquantitative reverse transcription PCR. Western blot and flow cytometry were performed to detect the surface PD-1 expression in T cells. Results: HNRNPK was screened as a key splicing factor that promoted PDCD1 exon 3 skipping, causing a decrease in flPD-1 expression on T cell membrane and an increase in sPD-1 expression. Mechanically, a key ESS has been identified on exon 3 and can be bound by HNRNPK protein to promote exon 3 skipping. Blocking the interaction between ESS and HNRNPK with an ASO significantly reduced exon 3 skipping. Importantly, HNRNPK can promote exon 3 skipping of mouse Pdcd1 gene as well. Conclusions: Our study revealed a novel evolutionarily conserved regulatory mechanism of PD-1 expression. The splicing factor HNRNPK markedly promoted PDCD1 exon 3 skipping by binding to the ESS on PDCD1 exon 3, resulting in decreased expression of flPD-1 and increased expression of sPD-1 in T cells. [ABSTRACT FROM AUTHOR]

Abstract Background Programmed cell death 1 (PD-1) belongs to immune checkpoint proteins ensuring negative regulation of the immune response. In non-small cell lung cancer (NSCLC), the sensitivity to treatment with anti-PD-1 therapeutics, and its efficacy, mostly correlated with the increase of tumor infiltrating PD-1+ lymphocytes. Due to solid tumor heterogeneity of PD-1+ populations, novel low molecular weight anti-PD-1 high-affinity diagnostic probes can increase the reliability of expression profiling of PD-1+ tumor infiltrating lymphocytes (TILs) in tumor tissue biopsies and in vivo mapping efficiency using immune-PET imaging. Methods We designed a 13 kDa β-sheet Myomedin scaffold combinatorial library by randomization of 12 mutable residues, and in combination with ribosome display, we identified anti-PD-1 Myomedin variants (MBA ligands) that specifically bound to human and murine PD-1-transfected HEK293T cells and human SUP-T1 cells spontaneously overexpressing cell surface PD-1. Results Binding affinity to cell-surface expressed human and murine PD-1 on transfected HEK293T cells was measured by fluorescence with LigandTracer and resulted in the selection of most promising variants MBA066 (hPD-1 KD = 6.9 nM; mPD-1 KD = 40.5 nM), MBA197 (hPD-1 KD = 29.7 nM; mPD-1 KD = 21.4 nM) and MBA414 (hPD-1 KD = 8.6 nM; mPD-1 KD = 2.4 nM). The potential of MBA proteins for imaging of PD-1+ populations in vivo was demonstrated using deferoxamine-conjugated MBA labeled with 68Galium isotope. Radiochemical purity of 68Ga-MBA proteins reached values 94.7–99.3% and in vitro stability in human serum after 120 min was in the range 94.6–98.2%. The distribution of 68Ga-MBA proteins in mice was monitored using whole-body positron emission tomography combined with computerized tomography (PET/CT) imaging up to 90 min post-injection and post mortem examined in 12 mouse organs. The specificity of MBA proteins was proven by co-staining frozen sections of human tonsils and NSCLC tissue biopsies with anti-PD-1 antibody, and demonstrated their potential for mapping PD-1+ populations in solid tumors. Conclusions Using directed evolution, we developed a unique set of small binding proteins that can improve PD-1 diagnostics in vitro as well as in vivo using PET/CT imaging. Graphical Abstract

Objective To investigate the effect of tumor-infiltrating B cells on the therapeutic efficacy of programmed death ligand-1 [PD-(L)1] inhibitors and elucidate the potential mechanisms. Methods Based on immunotherapy cohorts for melanoma patients in public databases, the relationship of B cells with progression-free survival (PFS) and response to immune checkpoint inhibitors treatment was analyzed. TC-1 and B16-OVA cells were implanted subcutaneously and in the liver in 6-8-week-old female C57BL/6 mice to establish tumor xenograft models. The effect of B cell clearance on PD-(L)1 therapy was compared. Flow cytometry was performed on the 15th day of TC-1 tumor microenvironment (TME) to confirm the number, function and phenotypic changes of T cells. Flow cytometry and quantitative real-time polymerase chain reaction (qPCR) were used to detect B cell surface molecules and cytokines. Results Based on ERP105482 data from the ICBatlas public database, high CD19 expression in the tumors was associated with longer PFS in melanoma patients (753 vs 95 d, HR=0.3, 95%CI: 0.13~0.65, P=0.003). B cells were significantly enriched in immunotherapy-responsive patients (P=0.01). In a mouse TC-1 liver-loaded tumor model, PD-(L)1 antibody treatment reduced tumor mass (P < 0.01), whereas B-cell clearance attenuated the therapeutic efficacy. B cells enhanced PD-(L)1 antibody treatment by promoting T cell infiltration and function, and the treatment resulted in changes in B cell subsets, as evidenced by an increase in PD-1 low-expressing subsets (P < 0.01). Conclusion After PD-(L)1 treatment, a decrease in PD-1 expression on B cell subsets might be one of the potential mechanisms by which B cells enhance the efficacy of PD-(L)1 therapy.

Introduction. Melanoma is the most dangerous neoplasm of the skin, characterized by a malignant and aggressive course. Transcriptional and growth factors, components of the AKT/mTOR signaling pathway, receptors and ligands of programmed cell death are involved in significant processes of oncogenesis.Aim. To study the expression of components of the AKT/mTOR (mTOR – mammalian target of rapamycin) signaling pathway, transcription and growth factors, expression of AMPK, LC3B, programmed cell death 1 (PD-1), programmed death-ligand 1 PD-L1 and programmed death-ligand 2 (PD-L2) in skin and mucosal tumor tissues.Materials and methods. The study included 21 patients with a verified diagnosis of melanoma of the skin of various localizations and mucous membranes of the nasal cavity T1a–4bN0M0 (I–IV stages) and 18 patients with basal cell carcinoma of the skin of various localizations T1–4N0M0 (I–VIA stages), aged 45 to 72 years old, who were treated in the department of head and neck tumors of the Cancer Research Institute, Tomsk National Research Medical Center. The presence of tumor ulceration was determined by microscopy and registration of the true absence of the epidermis over the tumor or due to traumatization of the epidermis. Expression of components of the AKT/mTOR signaling pathway, transcription and growth factors, expression of AMPK, LC3B, PD-1, PD-L1 and PD-L2 in the tumor tissue was determined by real-time polymerase chain reaction.Results. An increase in the expression of 70 S6 kinase and VHL was found in melanoma tissues compared to basal cell carcinoma. At the same time, the presence of signs of ulceration was associated with a low level of c-RAF, nuclear factor kappa B (NF-kB) p50 and hypoxia-inducible factor 1 (HIF-1) matrix RNA (mRNA) against the background of an increase in the expression of the hypoxia-inducible factor 2 (HIF-2) transcription factor. The study of the molecular features of neoplasms in relation to the tumor thickness according to Breslow revealed the contribution of transcription and growth factors, the intensity of intracellular signaling processes, modification of the microenvironment, autophagy and neoangiogenesis.Conclusion. The molecular and biological features of melanomas associated with invasive tumor growth have been identified. An increase in the expression of 70 S6 kinase and VHL are characteristic of a malignant skin tumor. The presence of signs of ulceration and tumor invasion were associated with a change in the transcriptional characteristics of factors with the induction of key markers, oncogenesis, which contributes to the formation of the invasive potential of the tumor.

Introduction: Breast cancer is the most common malignant tumour and the leading cause of cancer-related death in women is breast cancer. The Immunohistochemistry (IHC) method utilised antigens and antibodies to interact to identify cellular or tissue constituents (antigens). This research has been employed as a diagnostic tool for specific cancers. When Programmed Cell Death Ligand 1 (PD-L1) binds to Programmed Cell Death 1 (PD-1), it suppresses the cellular immune response by killing and depleting T-cells. Monoclonal antibodies that block the PD-1/ PD-L1 pathway have shown promise as a treatment strategy currently being tested in human cancer trials. Need for the study: Breast cancer is a global issue, and PDL1 expression is emerging as a promising biomarker for breast cancer prognosis. It can provide valuable information treatment planning. Aim: The current study aims to examine the expression of PD-1 and PD-L1 in breast cancer using IHC in all subgroups of breast cancer patients. Both tests can serve as a biomarkers to guide immunotherapeutic interventions, improving prognosis, and correlating with other clinicopathological individual parameters such as age, tumour size, distant metastasis, lymph node involvement, Estrogen Receptor (ER) and Progesterone Receptor (PR) status, Her2neu expression, histological type, and TNM stage. Materials and Methods: This will be a two-year cohort study conducted in the Department of Pathology, Jawaharlal Nehru Medical College (JNMC), Maharashtra, India. The study will include 70 specimens from all cases with a histopathological diagnosis of breast cancer. The Nottingham variant of the Bloom-Richardson Grading System will be used to determine the histological grade of the tumour, and immunostaining for PD-1 and PD-L1 will be performed to evaluate their protein expression.

BackgroundCreatinine-to-cystatin C ratio (CCR) and body composition (BC) parameters have emerged as significant prognostic factors in cancer patients. However, the potential effects of CCR in gastric cancer (GC) remains to be elucidated. This multi-center retrospective study explored the predictive and prognostic value of CCR and BC-parameters in patients with metastatic GC receiving PD-1 inhibitors-based combination therapy.MethodsOne hundred and thirteen GC patients undergoing PD-1 inhibitors-based combination therapy were enrolled at three academic medical centers from January 2021 to July 2023. A deep-learning platform based on U-Net was developed to automatically segment skeletal muscle index (SMI), subcutaneous adipose tissue index (SATI) and visceral adipose tissue index (VATI). Patients were divided into two groups based on the median of CCR or the upper tertile of BC-parameters. Logistic and Cox regression analysis were used to determine the effect of CCR and BC-parameters in predicting response rates and survival rates.ResultsThe CCR was positively correlated with SMI (r=0.43; P0.05). Multivariable logistic analysis identified that both low CCR (OR=0.423, P=0.066 for ORR; OR=0.026, P=0.005 for DCR) and low SATI (OR=0.270, P=0.020 for ORR; OR=0.149, P=0.056 for DCR) were independently associated with worse objective response rate (ORR) and disease control rate (DCR). Patients with low CCR or low SATI had significantly lower 8-month progression-free survival (PFS) rate and 16-month overall survival (OS) rate than those with high CCR (PFS rate, 37.6% vs. 55.1%, P=0.011; OS rate, 19.4% vs. 44.9%, P=0.002) or those with high SATI (PFS rate, 37.2% vs. 53.8%, P=0.035; OS rate, 8.0% vs. 36.0%, P

As the world’s fourth most deadly cancer, colorectal cancer (CRC) still needed the novel therapeutic drugs and target urgently. Although cyclin-dependent kinase 12 (CDK12) has been shown to be implicated in the malignancy of several types of cancer, its functional role and mechanism in CRC remain largely unknown. Here, we found that suppression of CDK12 inhibited tumor growth in CRC by inducing apoptosis. And CDK12 inhibition triggered autophagy by upregulating autophagy related gene 7 (ATG7) expression. Inhibition of autophagy by ATG7 knockdown and chloroquine (CQ) further decreased cell viability induced by CDK12 inhibition. Further mechanism exploration showed that CDK12 interacted with protein kinase B (AKT) regulated autophagy via AKT/forkhead box O3 (AKT/FOXO3) pathway. FOXO3 transcriptionally upregulated ATG7 expression and autophagy when CDK12 inhibition in CRC. Level of CDK12 and p-FOXO3/FOXO3 ratio were correlated with survival in CRC patients. Moreover, CDK12 inhibition improved the efficacy of anti-programmed cell death 1(PD-1) therapy in CRC murine models by enhancing CD8 + T cells infiltration. Thus, our study founded that CDK12 inhibition upregulates ATG7 triggering autophagy via AKT/FOXO3 pathway and enhances anti-PD-1 efficacy in CRC. We revealed the roles of CDK12/FOXO3/ATG7 in regulating CRC progression, suggesting potential biomarkers and therapeutic target for CRC.

Simple Summary: This research revealed that the downregulation of fumarate hydratase in patients is associated with poor prognosis. Mechanistically, FH binds to RAN, which inhibits the nuclear import of the PCSK9 transcription factor SREBF1/2, thus reducing the expression of PCSK9. This leads to increased clonal expansion of CD8+ T cells while the number of Tregs remains unchanged, and the expression of PD-L1 does not change significantly, thus enhancing the immunotherapy response. Importantly, combined therapy targeting PCSK9 and PD-1 may be beneficial for patients with CRC and low FH expression. Considering these results, our findings hold potential for future clinical applications. Despite the notable achievements of programmed death 1 (PD-1) antibodies in treating various cancers, the overall efficacy remains limited in the majority of colorectal cancer (CRC) cases. Metabolism reprogramming of tumors inhibits the tricarboxylic acid (TCA) cycle, leading to down-regulation of fumarate hydratase (FH), which is related to poor prognosis in CRC patients. By establishing a tumor-bearing mouse model of CRC with Fh1 expression deficiency, we confirmed that the therapeutic effect of PD-1 antibodies alone was suboptimal in mice with low Fh1 expression, which was improved by combination with a protein invertase subtilisin/kexin 9 (PCSK9) inhibitor. Mechanistically, FH binds to Ras-related nucleoprotein (RAN), which inhibits the nuclear import of the PCSK9 transcription factor SREBF1/2, thus reducing the expression of PCSK9. This leads to increased clonal expansion of CD8+ T cells while the number of Tregs remains unchanged, and the expression of PD-L1 does not change significantly, thus enhancing the immunotherapy response. On the contrary, the expression of PCSK9 increased in CRC cells with low FH expression, which antagonized the effects of immunotherapy. Overall, CRC patients with low FH expression may benefit from combinatorial therapy with PD-1 antibodies and PCSK9 inhibitors to enhance the curative effect. [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. The programmed cell death 1 (PDCD1) gene, which encodes the PD1 protein, is one of the many genes involved in susceptibility to SLE. The PD1 protein is an inhibitory immunoreceptor that plays a key role in maintaining immunological tolerance to self-antigens. The PD1.5 C/T polymorphism (rs2227981, c.804 T > C) alters the expression and function of the PD-1 receptor. Objectives: This case-control study aimed to determine the association between the rs2227981 polymorphism of the PDCD1 gene and susceptibility to SLE in the northwestern population of Iran. Methods: The rs2227981 genotype was determined in 52 SLE patients and 53 controls using the PCR-RFLP method with the Pvu II restriction enzyme. Results: The study found a significant association between the rs2227981 polymorphism and susceptibility to SLE in the study population. Conclusions: The rs2227981 polymorphism appears to be a risk factor for SLE in northwestern Iran. [ABSTRACT FROM AUTHOR]

This study aims to determine the prognostic significance of programmed cell death ligand 1 (PD-L1) expression and tumour-infiltrating lymphocytes (TILs) in triple- negative breast cancer (TNBC). PD-L1 expression and TIL percentage were determined in TNBCs that did not receive neoadjuvant therapy. The relationship between PD-L1 expression and the percentage of TILs with survival was investigated. The presence of intratumoural PD-L1-positive tumour-infiltrating immune cells (TIICs) in tumours with ≥ 1% PD-L1 expression was identified as a new PD-L1 evaluation parameter. The presence of intratumoural PD-L1-positive TIICs as a new parameter in PD-L1-positive cases increased overall survival. The percentage of TILs increased in both overall and distant metastasis-free survival (p = 0.040 and p = 0.006, respectively). As a result, it was found that the risk of death was increased 5.18-fold (p = 0.013) in patients without intratumoural PD-L1-positive TIICs. This risk of death was calculated to be 5.40-fold higher in patients with TIL percentage ≤ 10% than in those with > 40% (p = 0.024), and the risk of distant metastasis was calculated to be 11.95 times higher. In our study, we discovered that the percentage of TILs made a statistically significant difference in TNBC survival. The presence of intratumoural PD-L1-positive TIICs in PD-L1-positive cases significantly increased survival.

The programmed cell death 1 protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis plays a crucial role in tumor immunosuppression, while the cancer-associated fibroblasts (CAFs) have various tumor-promoting functions. To determine the advantage of immunotherapy, the relationship between the cancer cells and the CAFs was evaluated in terms of the PD-1/PD-L1 axis. Overall, 140 cases of esophageal cancer underwent an immunohistochemical analysis of the PD-L1 expression and its association with the expression of the α smooth muscle actin, fibroblast activation protein, CD8, and forkhead box P3 (FoxP3) positive cells. The relationship between the cancer cells and the CAFs was evaluated in vitro, and the effect of the anti-PD-L1 antibody was evaluated using a syngeneic mouse model. A survival analysis showed that the PD-L1+ CAF group had worse survival than the PD-L1- group. In vitro and in vivo, direct interaction between the cancer cells and the CAFs showed a mutually upregulated PD-L1 expression. In vivo, the anti-PD-L1 antibody increased the number of dead CAFs and cancer cells, resulting in increased CD8+ T cells and decreased FoxP3+ regulatory T cells. We demonstrated that the PD-L1-expressing CAFs lead to poor outcomes in patients with esophageal cancer. The cancer cells and the CAFs mutually enhanced the PD-L1 expression and induced tumor immunosuppression. Therefore, the PD-L1-expressing CAFs may be good targets for cancer therapy, inhibiting tumor progression and improving host tumor immunity. [ABSTRACT FROM AUTHOR]

Introduction: Breast cancer is the most common malignant tumour and the leading cause of cancer-related death in women is breast cancer. The Immunohistochemistry (IHC) method utilised antigens and antibodies to interact to identify cellular or tissue constituents (antigens). This research has been employed as a diagnostic tool for specific cancers. When Programmed Cell Death Ligand 1 (PD-L1) binds to Programmed Cell Death 1 (PD-1), it suppresses the cellular immune response by killing and depleting T-cells. Monoclonal antibodies that block the PD-1/PD-L1 pathway have shown promise as a treatment strategy currently being tested in human cancer trials. Need for the study: Breast cancer is a global issue, and PDL1 expression is emerging as a promising biomarker for breast cancer prognosis. It can provide valuable information treatment planning. Aim: The current study aims to examine the expression of PD-1 and PD-L1 in breast cancer using IHC in all subgroups of breast cancer patients. Both tests can serve as a biomarkers to guide immunotherapeutic interventions, improving prognosis, and correlating with other clinicopathological individual parameters such as age, tumour size, distant metastasis, lymph node involvement, Estrogen Receptor (ER) and Progesterone Receptor (PR) status, Her2neu expression, histological type, and TNM stage. Materials and Methods: This will be a two-year cohort study conducted in the Department of Pathology, Jawaharlal Nehru Medical College (JNMC), Maharashtra, India. The study will include 70 specimens from all cases with a histopathological diagnosis of breast cancer. The Nottingham variant of the Bloom-Richardson Grading System will be used to determine the histological grade of the tumour, and immunostaining for PD-1 and PD-L1 will be performed to evaluate their protein expression. [ABSTRACT FROM AUTHOR]

Background: The level of C‑reactive protein (CRP) and alpha‑fetoprotein (AFP) in immunotherapy (CRAFITY) score was associated with the prognosis of hepatocellular carcinoma (HCC) patients treated with immunotherapy. Based on the CRAFITY score, this study aimed to investigate the efficacy and safety of locoregional-immunotherapy for treating HCC patients. Methods: HCC patients who received locoregional-immunotherapy were consecutively recruited at Sun Yat-sen University Cancer Center in 2019. CRAFITY 0 score was defined as the AFP level below 100 ng/ml and a CRP level of less than 1 mg/dl, CRAFITY 1 score was defined as the AFP level of at least 100 ng/ml or the CRP level of at least 1 mg/dl, and CRAFITY 2 score was defined as both the AFP level over 100 ng/ml and the CRP level of more than 1 mg/dl. The primary outcomes were progression-free survival (PFS) and overall survival (OS). The second outcomes were tumor response rate and treatment-related adverse events (AEs). Results: The median PFS for HCC patients with the CRAFITY 0 score was not estimable. The PFS was 11.0 months [95% confidence interval (CI) 7.2–14.9] and 6.0 months (95% CI 4.2–7.8) for patients with CRAFITY 1 and 2 scores, respectively, with a significant difference between the two groups (p < 0.001). HCC patients with CRAFITY 0, 1, and 2 scores had 3 years OS rates of 63.8%, 60.8%, and 32.1%, respectively, with statistical differences among the three groups (p < 0.001). Patients with the CRAFITY 2 score were more likely to experience fever than those with other scores (p < 0.05). A greater CRAFITY score was correlated with a higher incidence of grade 3 and above liver injury (p < 0.01). Conclusions: The CRAFITY score is a superior predictor of prognosis and treatment-related AEs in HCC patients treated with locoregional-immunotherapy. [ABSTRACT FROM AUTHOR]

This study aims to investigate changes in the tumor immune environment of patients who underwent therapy with a vascular endothelial growth factor (VEGF) inhibitor for advanced colorectal cancer. Patients (n = 135) with T3 or T4 colorectal cancer were included in this retrospective study. They were classified as follows: patients who had not received preoperative treatment (UPFRONT group, n = 54), who had received FOLFOX as preoperative chemotherapy (FOLFOX group, n = 55), and who had undergone resection after combination FOLFOX and bevacizumab as unresectable colorectal cancer (B-MAB group, n = 26). The number of cytotoxic T lymphocytes (CTLs), FOXP3+ lymphocytes (including regulatory T cells (Tregs)), CD163+ monocytes (including M2-type tumor-associated macrophages (TAM-M2 type)), and programmed cell death 1 (PD-1)+ lymphocytes was evaluated immunohistochemically in the cancer cell area (CC) and stromal cell area (ST) of surgical specimens, and compared among the three groups. The CTL population did not differ among the three groups in both areas. In the B-MAB group, the numbers of PD-1+ cells in the ST, FOXP3+ lymphocytes in both areas, and CD163+monocytes in the ST was lower than that in the other two groups, and a correlation with the histological therapeutic effect was observed. In advanced colorectal cancer, VEGF inhibitors may decrease the number of PD-1+ cells and inhibit the infiltration of FOXP3+ lymphocytes and CD163+monocytes into the tumor environment. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have emerged as a revolutionary treatment option for patients with various types of malignancy. Although these agents afford a significant improvement in outcomes for melanoma and other previously untreatable malignancies, their novel mechanism of action may predispose patients to immune-related adverse effects (irAEs). In the tumour neoantigen environment, these irAEs are due to the activation of the immune system by the blockade of suppressive checkpoints, leading to increases in T-cell activation and proliferation. IrAEs have been reported in almost any organ and at any point in time, even months to years after discontinuation of therapy. Certain populations with distinct physiological changes, genetic risk factors, and specific antigen exposures may be more highly predisposed to develop irAEs. This review discusses the incidence and mechanisms of irAEs and the relationship between host factors and irAE occurrence.

Immune checkpoint inhibitors (ICIs), including cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and its ligand 1 (PD-L1), have improved the survival in multiple types of cancers; however, ICIs may cause cardiovascular toxicity. Although rare, ICI-mediated cardiotoxicity is an extremely serious complication with a relatively high mortality. In this review, we discuss the underlying mechanism and clinical manifestations of cardiovascular toxicity induced by ICIs. According to previous studies, multiple signaling pathways are involved in myocarditis induced by ICIs. Further, we summarize the clinical trials of drugs for the treatment of ICI-associated myocarditis. Although these drugs have shown the beneficial effects of alleviating cardiac function and reducing mortality rates, their efficacy is not optimal. Finally, we discuss the therapeutic potential of some novel compounds as well as the underlying mechanisms of their action. [ABSTRACT FROM AUTHOR]

Sepsis is a multiple organ dysfunction syndrome caused by the host's immune response to infection, with extremely high incidence and mortality. Immunosuppression is an essential pathophysiological alteration that influences the clinical treatment and prognosis of sepsis. Recent studies have suggested that the programmed cell death 1 signaling pathway is involved in the formation of immunosuppression in sepsis. In this review, we systematically present the mechanisms of immune dysregulation in sepsis and elucidate the expression and regulatory effects of the programmed cell death 1 signaling pathway on immune cells associated with sepsis. We then specify current research developments and prospects for the application of the programmed cell death 1 signaling pathway in immunomodulatory therapy for sepsis. Several open questions and future research are discussed at the end. [ABSTRACT FROM AUTHOR]

Simple Summary: The immunological profile of pleomorphic invasive lobular cancer is poorly investigated. pILC is characterized by more aggressive behavior and a worse prognosis; however, this rare subtype lacks a specific treatment approach. Here, we investigated the expression of sTILs and analyzed the PD-L1 expression levels from sixty-six patients with pILC. Moreover, we analyzed the association between sTILs and PD-L1 expression with other prognostic or predictive biomarkers and correlated sTILs and PD-L1 expression with survival outcomes. sTILS (≥1%) was present in 64% of the patients, and 36% of the tumors demonstrated a positive PD-L1 using SP142 (≥1%) and 28% had a positive PD-L1 score of ≥1 using 22C3. We found no differences between the molecular subtypes, the clinicopathological features, and the immune parameters, probably due to the small sample size of the HER2+ and TN subgroups. Larger trials on the immune composition of the subtypes of lobular breast cancer are needed. Background: The prognostic and predictive role of stromal tumor-infiltrating lymphocytes (sTILs) is undetermined in pleomorphic invasive lobular cancer (pILC). The same applies for the expression of PD-1/PD-L1 in this rare breast cancer subtype. Here, we aimed to investigate the expression of sTILs and analyze the PD-L1 expression levels in pILC. Methods: Archival tissues from sixty-six patients with pILC were collected. The sTIL density was scored as a percentage of tumor area using the following cut-offs: 0%; <5%; 5–9%; and 10–50%. The PD-L1 expression was analyzed using IHC on formalin-fixed, paraffin-embedded tissue sections using SP142 and 22C3 antibodies. Results: A total of 82% of the sixty-six patients were hormone receptor positive and 8% of cases were triple negative (TN), while 10% showed human epidermal growth factor receptor 2 (HER2) amplification. sTILs (≥1%) were present in 64% of the study population. Using the SP142 antibody, 36% of tumors demonstrated a positive PD-L1 score of ≥1%, and using the 22C3 antibody, 28% had a positive PD-L1 score of ≥1. There was no correlation between sTILs or PD-L1 expression and tumor size, tumor grade, nodal status, expression of estrogen receptor (ER), or amplification of HER2. Our data did not show any difference in survival between the three molecular subtypes of pILC with respect to sTILs and PD-L1 expression. Conclusion: This study shows that pILCs show some degree of sTILs and PD-L1 expression; however, this was not associated with a survival improvement. Additional large trials are needed to understand immune infiltration in lobular cancer, especially in the pleomorphic subtype. [ABSTRACT FROM AUTHOR]

Keratinocytic cancers (KCs), specifically cutaneous squamous cell and basal cell carcinomas, can respond to topical, intralesional, or systemic immunotherapies, but cutaneous adverse events (CAEs) may occur. Understanding these risks, early recognition of these CAEs, and effective treatment may enable patients to continue their anticancer immunotherapies without dose impact. Immune checkpoint inhibitor-related CAEs after KCs can have multiple clinical presentations, with specific observed types including psoriasis and bullous pemphigoid. Cutaneous toxicities can require biopsies to confirm the diagnosis, especially in patients who are not responsive to topical or oral steroids, since the selection of biologic drugs depends on accurate diagnosis. Different types of CAEs from immune checkpoint inhibitors have been associated with different oncologic outcomes in various primary cancer types, and this remains to be determined for KC patients. CAE characterization and management after immune checkpoint inhibitors in KC patients is a rapidly growing field that needs specific and prospective studies. [ABSTRACT FROM AUTHOR]

The important role of the immune system in the surveillance and control of keratinocyte cancers (KCs), namely squamous and basal cell carcinomas, is increasingly appreciated, as new immunotherapies have recently become available. As the field of immunotherapy is rapidly evolving, this review synthesizes key concepts and highlights important cellular components within the immune system responsible for attacking KCs. We review the most current data on the epidemiology, risk factors, and immunotherapy management for KCs. Patients will seek advice from dermatologists to help explain why immunotherapies work for KCs and whether they might be appropriate for different clinical scenarios. Collaboration with medical colleagues across different disciplines to evaluate KCs for response to immunotherapy and early recognition of immune-related adverse events will help to optimize patient outcomes. [ABSTRACT FROM AUTHOR]

Gastric cancer treatments are evolving rapidly. For example, immune checkpoint inhibitors, especially those that target PD-1 or PD-L1, have long-term efficacy in a subset of gastric cancer patients, and are currently the first-line therapy. Immunotherapies approved for use in untreated gastric cancer patients include monotherapy and chemotherapy-immunotherapy combinations. Major clinical trials have reported efficacy and safety data suggesting that PD-L1 expression is important for regimen selection, although other biomarkers, clinicopathologic factors, and patient preference might also be relevant in other situations. Currently, several novel biomarkers and therapeutic strategies are being assessed, which might refine the current treatment paradigm. In this review, we describe the current treatment regimens for patients with gastric cancer and detail the approach we use for the selection of first-line immunotherapy regimens. [ABSTRACT FROM AUTHOR]

Background and purpose: The clinical role of postoperative adjuvant therapy in hepatocellular carcinoma (HCC) is still unclear. The purpose of our study was to explore the clinical value of postoperative adjuvant anti-programed cell death 1 antibody (PA-PD-1) on the prognosis of HCC patients with high relapse risks after surgery. Patients and methods: Data of consecutive HCC patients with high recurrence risks treated with liver resection at our center during January 2019 and March 2021 were prospectively collected. Baseline differences were balanced between HCC patients with (PA-PD-1 group) or without PA-PD-1 (non-PD-1 group) after hepatectomy by propensity-score matching (PSM). Between these two groups, we compared overall survival (OS) and recurrence-free survival (RFS). Independent prognostic risk factors for OS and RFS were confirmed by Cox regression analysis, and subgroup analysis was also performed. Results: 47 pairs of patients with or without PD-1 treatment after hepatectomy were matched. After PSM, the 1-year and 2-year RFS was 58.4% and 44.1% in the PA-PD-1 group, and 34.0% and 21.3% in the non-PD-1 group (p = 0.008). The OS at 1 year and 2 years was 91.2% and 91.2% in the PA-PD-1 group, compared with 85.1% and 61.7% in the non-PD-1 group (p = 0.024). Multivariable analyses demonstrated that PA-PD-1 was an independent protective predictor associated with RFS and OS. Through subgroup analysis, we concluded that HCC patients with portal venous tumor thrombus (PVTT) or tumor size ≥ 5 cm significantly benefited from PA-PD-1 therapy in RFS and OS. Conclusions: Adjuvant anti-PD-1 antibody can effectively improve the survival outcomes of HCC patients with high relapse risks after hepatectomy in this prospective observational study. This finding should be confirmed by results of the ongoing phase 3 randomized controlled trials. [ABSTRACT FROM AUTHOR]

This study aims to determine the prognostic significance of programmed cell death ligand 1 (PD-L1) expression and tumour-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC). PD-L1 expression and TIL percentage were determined in TNBCs that did not receive neoadjuvant therapy. The relationship between PD-L1 expression and the percentage of TILs with survival was investigated. The presence of intratumoural PD-L1-positive tumour-infiltrating immune cells (TIICs) in tumours with ≥ 1% PD-L1 expression was identified as a new PD-L1 evaluation parameter. The presence of intratumoural PD-L1-positive TIICs as a new parameter in PD-L1-positive cases increased overall survival. The percentage of TILs increased in both overall and distant metastasis-free survival (p = 0.040 and p = 0.006, respectively). As a result, it was found that the risk of death was increased 5.18-fold (p = 0.013) in patients without intratumoural PD-L1-positive TIICs. This risk of death was calculated to be 5.40-fold higher in patients with TIL percentage ≤ 10% than in those with > 40% (p = 0.024), and the risk of distant metastasis was calculated to be 11.95 times higher. In our study, we discovered that the percentage of TILs made a statistically significant difference in TNBC survival. The presence of intratumoural PD-L1-positive TIICs in PD-L1-positive cases significantly increased survival. [ABSTRACT FROM AUTHOR]

The development of checkpoint inhibitors has redefined the treatment paradigm for advanced gastroesophageal cancer. While recent developments have improved clinical outcomes, the prognosis for the disease remains meager. In this review, we discuss the rationale and detail the results from recent phase I-III trials supporting the activity of PD-1 inhibitors. Specifically, we highlight the seminal clinical trials leading to the FDA approval of pembrolizumab for advanced gastroesophageal cancer. Finally, we review the current understanding and future considerations of molecular subtyping and predictive biomarkers to help guide therapy and the promise of combination therapy to further improve the efficacy of checkpoint inhibitors.

Increased incidence of breast cancer has stimulated development of new diagnostic and therapeutic methods. The programmed cell death 1 (PD1) pathway and its inhibitors are promising avenues for investigation. PD1 includes PD ligands 1 (PDL1) and 2 (PDL2). We investigated the expression of PD1 and PDL1 in invasive breast carcinomas using immunohistochemical staining. We used 171 invasive breast carcinoma specimens from which tissue microarray blocks were created. Immunohistochemical staining of PD1 using NAT105, and PDL1 using CAL10 was performed on tissue microarray sections. NAT105 and CAL10 are useful clones for detecting expression of PD1 and PDL1. PD1 and PDL1 immunostaining was significantly stronger in carcinomas with basal-like phenotype compared to other molecular breast cancer types. PD1 and PDL1 expression also was associated with a high histologic grade and a high Ki-67 index. PD1 expression also was associated with lymphovascular invasion and axillary metastasis. PD1 and PDL1 expression is associated with aggressive tumor behavior and a basal-like phenotype in breast cancer. We suggest that inhibition of the PD1/PDL1 pathway, particularly in triple negative breast carcinomas with basal-like phenotype, might be useful for targeted immunotherapy. [ABSTRACT FROM AUTHOR]

The use of adjuvant therapy has provided survival benefits in patients with advanced melanoma. This study aimed to explore the recurrence and prognosis of the PD-1 inhibitor, conventional interferon (IFN), or observation (OBS) on resected stage III acral and cutaneous melanoma patients through a retrospective analysis. Patients with resected stage III melanoma at Fudan University Shanghai Cancer Center from 2017 to 2021 were enrolled with all of their clinicopathologic characteristics collected. They were divided into three groups: PD-1 inhibitor, IFN, and OBS. Survival analyses were performed to indicate the significance of different adjuvant therapies. A total of 199 patients were enrolled (PD-1 n = 126; IFN n = 31; and OBS n = 42), with their median follow-up times being 21 months, 24 months, and 49 months, respectively. The PD-1 inhibitor significantly improved relapse-free survival (p = 0.027) and overall survival (p = 0.033) compared with conventional treatment (IFN+OBS). The superiority of the PD-1 inhibitor was witnessed in stage IIIC/D (p = 0.000) acral (p = 0.05) melanoma patients with ulceration (p = 0.011) or lymph node macrometastasis (p = 0.010). The PD-1 inhibitor significantly reduced local recurrence and systemic metastasis compared with conventional therapy (p = 0.002). In conclusion, adjuvant anti-PD-1 immunotherapy can achieve better survival outcomes in acral and cutaneous melanoma patients compared with conventional treatment, without considering adverse events. More clinical benefits were seen in later-stage acral melanoma patients with ulceration or lymph node macrometastasis. [ABSTRACT FROM AUTHOR]

Background: Programmed cell death 1(PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an immune checkpoint implicated in immune tolerance and involved in the pathogenesis of several autoimmune diseases. Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple immune dysregulation. This study aimed to determine PD-1 and PD-L1 expressed levels on both CD3 T and CD19 B lymphocytes in SLE patients compared to healthy donors and their associations with the clinical data and disease activity of those patients. Patients and Methods: A total of 25 healthy donors and 80 SLE patients were involved in the study. PD-1 and PD-L1 expressed levels on each of CD3 T and CD19 B lymphocytes were determined in the peripheral blood (PB) using flow cytometry. Results: The expressed levels of PD-1 and PD-L1 on both CD3 T and CD19 B lymphocytes were significantly higher in PB of SLE group than that of controls (P = 0.01, P = 0.001, P = 0.009, and P = 0.001). Significant positive associations were found between PD-1 and PD-L1 expressions on both CD3 T and CD19 B lymphocytes with disease activity in SLE group (P < 0.05). Conclusion: PD-1 and its ligand PD-L1 could have a role as regulators for immune activation in patients with SLE. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is the most common form of liver cancer that has limited treatment options and a poor prognosis. Transarterial chemoembolization (TACE) is the first-line treatment for intermediate-stage HCC but can induce tumour hypoxia, thereby promoting angiogenesis. Recent studies suggested that combining TACE with anti-angiogenic therapies and immunotherapy might improve efficacy. Lenvatinib, a tyrosine kinase inhibitor, has demonstrated superior outcomes compared to sorafenib, while immune checkpoint inhibitors such as sintilimab show potential when combined with TACE. However, the efficacy and safety of TACE combined with lenvatinib and sintilimab (TACE + SL) compared to TACE with lenvatinib alone (TACE + L) in patients with intermediate-advanced HCC has not yet been investigated., Aim: To evaluate the efficacy and safety of TACE + SL therapy in comparison to TACE + L therapy in patients with intermediate-advanced HCC., Methods: A retrospective analysis was performed on patients with intermediate-advanced HCC who received TACE plus lenvatinib with or without sintilimab between September 2019 and September 2022. Baseline characteristics were compared, and propensity score matching was applied. Overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were evaluated between the two groups, and adverse events were analyzed., Results: The study included 57 patients, with 30 in the TACE + SL group and 27 in the TACE + L group. The TACE + SL group demonstrated significantly improved median PFS and OS compared to the TACE + L group (PFS: 14.1 months vs 9.6 months, P = 0.016; OS: 22.4 months vs 14.1 months, P = 0.039), along with a higher ORR (70.0% vs 55.6%). After propensity score matching, 30 patients were included, with the TACE + SL group again showing longer median PFS and a trend toward improved OS (PFS: 14.6 months vs 9.2 months, P = 0.012; OS: 23.9 months vs 16.3 months, P = 0.063), and a higher ORR (73.3% vs 53.3%). No severe adverse events were reported., Conclusion: TACE + SL demonstrated superior outcomes in terms of OS and PFS, compared to TACE + L. These findings suggest that the addition of sintilimab might enhance the therapeutic response in patients with intermediate-advanced HCC., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.)

This article discusses the article written by Tan et al . Transarterial chemoembolization (TACE) is one of the main treatment methods for advanced hepatocellular carcinoma (HCC). There are other vascular interventional therapies, including drug-eluting bead TACE, transarterial radioembolization, and hepatic arterial infusion chemotherapy. TACE combined with anti-angiogenesis therapy may improve tumor control and prolong progression free survival. The combination therapy of TACE and immunotherapy may improve the clinical efficacy of HCC. In future research, more basic and clinical studies are needed to explore the immunogenic intervention therapy., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Programmed cell death 1(PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an immune checkpoint implicated in immune tolerance and involved in the pathogenesis of several autoimmune diseases. Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple immune dysregulation. This study aimed to determine PD-1 and PD-L1 expressed levels on both CD3 T and CD19 B lymphocytes in SLE patients compared to healthy donors and their associations with the clinical data and disease activity of those patients. Patients and Methods: A total of 25 healthy donors and 80 SLE patients were involved in the study. PD-1 and PD-L1 expressed levels on each of CD3 T and CD19 B lymphocytes were determined in the peripheral blood (PB) using flow cytometry. Results: The expressed levels of PD-1 and PD-L1 on both CD3 T and CD19 B lymphocytes were significantly higher in PB of SLE group than that of controls (P = 0.01, P = 0.001, P = 0.009, and P = 0.001). Significant positive associations were found between PD-1 and PD-L1 expressions on both CD3 T and CD19 B lymphocytes with disease activity in SLE group (P < 0.05). Conclusion: PD-1 and its ligand PD-L1 could have a role as regulators for immune activation in patients with SLE.

Cancer is the second leading cause of death worldwide. Traditional approaches, such as surgery, chemotherapy, and radiotherapy have been the main cancer therapeutic modalities in recent years. Cancer immunotherapy is a novel therapeutic modality that potentiates the immune responses of patients against malignancy. Immune checkpoint proteins expressed on T cells or tumor cells serve as a target for inhibiting T cell overactivation, maintaining the balance between self-reactivity and autoimmunity. Tumors essentially hijack the immune checkpoint pathway in order to survive and spread. Immune checkpoint inhibitors (ICIs) are being developed as a result to reactivate the anti-tumor immune response. Recent advances in nanotechnology have contributed to the development of successful, safe, and efficient anticancer drug systems based on nanoparticles. Nanoparticle-based cancer immunotherapy overcomes numerous challenges and offers novel strategies for improving conventional immunotherapies. The fundamental and physiochemical properties of nanoparticles depend on various cancer therapeutic strategies, such as chemotherapeutics, nucleic acid-based treatments, photothermal therapy, and photodynamic agents. The review discusses the use of nanoparticles as carriers for delivering immune checkpoint inhibitors and their efficacy in cancer combination therapy. [ABSTRACT FROM AUTHOR]

Introduction: The treatment of non-small cell lung cancer (NSCLC) has profoundly changed on account of the arrival of new therapies, like immunotherapy. Within this group of drugs, those aimed at the programmed cell death-1 or programmed cell death ligand-1(PD1/PDL-1) are very relevant, for example, Pembrolizumab. Although its adverse reactions are generally mild and well tolerated, it has been associated with certain immune-related adverse events (IrAEs) than can be serious and affect any organ. Case report: A 62-year-old woman diagnosed with stage IV NSCLC with a single bone metastasis and PD-L1 expression of 60% started treatment with cisplatin-pemetrexed-pembrolizumab, and maintenance with pembrolizumab. Management and outcome: The patient attended the ER with pericardial effusion that was assumed to be a Pembrolizumab IrAE and was managed with corticosteroids. The patient fully recovered but immunotherapy was not reintroduced due to the severity of the AE. Discussion: The cardiovascular system is among the least affected organs by immunotoxicity, with an incidence between 0.09–0.6%. However, some authors suspect the incidence is underestimated. Median time to onset is highly variable, ranging from 6 weeks since the first dose to 2 years after discontinuation of the treatment. There are not guidelines on the most effective management of the IrAEs, but according to the pharmaceutical reference, corticosteroids should be initiated followed by a progressive reduction. If no response is obtained, another immunosuppressive agent should be added. The determination to restart immunotherapy depends on the severity of the adverse reaction, the availability of other alternative treatments, and the cancer response. [ABSTRACT FROM AUTHOR]

Background: The specific efficacy of immunotherapy for patients with liver metastases of gastric cancer is unclear. This study set out to explore the treatment response and related prognostic factors for patients with liver metastases of gastric cancer treated with immunotherapy. Patients and methods: This retrospective cohort study included 135 patients with unresectable advanced gastric cancer. According to the presence of liver metastases and/or first-line treatment with immunotherapy, patients were divided into the following three groups: I-LM(-) group(patients without liver metastases treated with immunotherapy, n=66), I-LM(+) group(patients with liver metastases treated with immunotherapy, n=36), C-LM(+) group(patients with liver metastases treated with chemotherapy and/or target therapy, n=33). Cox regression analyses were used to identify factors associated with survival in all patients and the three groups, respectively. Results: For the patients with liver metastases treated with immunotherapy, multivariate analysis showed that only the presence of peritoneal metastases was significantly associated with shorter PFS [hazard ratios (HR), 3.23; 95% CI, 1.12-9.32; P=0.030] and the patients with peritoneal metastases had shorter median PFS than patients without peritoneal metastases(3.1 vs 18.4 months; P=0.004), while the objective response rate was 100% in patients with HER2-positive (2 complete radiographic responses and 2 partial responses; 3 of 4 patients were still ongoing benefits [median follow-up time, 15.3 months; interquartile range(IQR), 6.3-17.9 months]). Conclusions: The findings suggest that patients with various types of gastric cancer liver metastases respond differently to immune checkpoint inhibitors, HER2-positive patients may derive clinical benefits from immune checkpoint inhibitors, while the presence of peritoneal metastases is associated with resistance. [ABSTRACT FROM AUTHOR]