Anti-programmed Cell Death Ligand Research Articles

Immune microenvironment of Epstein-Barr virus (EBV)-negative compared to EBV-associated gastric cancers: implications for immunotherapy

BackgroundGastric carcinomas (GC) are aggressive malignancies, and only ~15% of patients respond to anti-programmed cell death (ligand) 1 (PD-(L)1) monotherapy. However, Epstein-Barr virus (EBV)-associated GCs (~5–10% of GCs) often harbor...

Seasonal influences on the efficacy of anti-programmed cell death (ligand) 1 inhibitors in lung cancer.

Seasonal variations in systemic immunity have been reported. This study aimed to evaluate whether seasonality affects the efficacy of anticancer immunotherapy. A total of 604 patients with lung cancer receiving single anti-programmed cell death (ligand) 1 (anti-PD-[L]1) inhibitors from two prospective observational cohorts were screened. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Patients were classified into two groups according to the season when the treatment started: winter (November-February) and other seasons (March-October). Kaplan-Meier analysis and Cox proportional hazards models were fitted to evaluate the impact of seasonality on survival. For validation, propensity score matching was performed. A total of 484 patients with advanced non-small cell lung cancer were included. In an unmatched population, multivariable analysis demonstrated that the winter group (n=173) had a significantly lower risk of progression or death from immunotherapy than the other group (n=311) (PFS: hazard ratio [HR],0.77 [95% confidence interval (CI), 0.62-0.96]; p=.018; OS: HR,0.77 [95% CI, 0.1-0.98]; p=.032). In a propensity score-matched population, the winter group (n=162) showed significantly longer median PFS (2.8 months [95% CI, 1.9-4.1 months] vs. 2.0 months [95% CI, 1.4-2.7 months]; p=.009) than the other group (n=162). The winter group's median OS was also significantly longer than that of the other group (13.4 months [95% CI, 10.2-18.0 months] vs. 8.0 months [95% CI, 3.6-8.7 months]; p=.012). The trend toward longer survival in the winter group continued in subgroup analyses. Starting an anti-PD-(L)1 inhibitor in winter was associated with better treatment outcomes in patients with lung cancer compared to other seasons.

The Phase 3 KEYLYNK-006 Study of Pembrolizumab Plus Olaparib Versus Pembrolizumab Plus Pemetrexed as Maintenance Therapy for Metastatic Nonsquamous NSCLC

IntroductionPoly (adenosine diphosphate–ribose) inhibitors, including olaparib, upregulate programmed cell death ligand 1, which may increase the efficacy of anti–programmed cell death ligand 1 therapies. MethodsIn the phase 3 KEYLYNK-006 trial (NCT03976323), eligible adults with previously untreated metastatic nonsquamous NSCLC without targetable genetic alterations who had complete response, partial response, or stable disease after induction therapy with four cycles of pembrolizumab 200 mg every three weeks, pemetrexed 500 mg/m2, and carboplatin AUC5 or cisplatin 75 mg/m2 were randomized in a one-to-one ratio to olaparib 300 mg orally twice daily or pemetrexed every three weeks, both given with 31 cycles or less of pembrolizumab every three weeks. Dual primary endpoints were progression-free survival (PFS) and overall survival (OS). Progression-free survival was tested at interim analysis 2 (i.e., final PFS analysis) and OS at final analysis (FA). ResultsOf 1003 patients who received induction therapy, 672 (67.0%) were randomized to pembrolizumab plus olaparib (n = 337) or pembrolizumab plus pemetrexed (n = 335) in the intention-to-treat population. Median follow-up at FA was 39.9 (range: 28.1–51.5) months. At interim analysis 2, the median (95% confidence interval [CI]) PFS was 7.1 (5.6–8.7) months versus 8.3 (6.9–11.5) months in the olaparib versus pemetrexed groups (hazard ratio = 1.12, 95% CI: 0.92–1.36, p = 0.87). At FA, the median (95% CI) OS was 20.7 (18.0–24.8) months versus 23.0 (19.0–26.4) months (hazard ratio = 1.04, 95% CI: 0.87–1.25, p = 0.6649). Grade 3 to 5 maintenance treatment-related adverse events occurred in 26.1% versus 30.1% of patients, respectively. ConclusionPembrolizumab plus maintenance olaparib did not improve PFS or OS versus pembrolizumab plus pemetrexed in previously untreated metastatic nonsquamous NSCLC without targetable genetic alterations.

Association Between Multisystem Immune-related Adverse Events and Progression-free Survivals in PD-1/PD-L1 Inhibitor Monotherapy.

Immune-related adverse events (irAEs) occur in various organs, and sometimes multiply following treatment with immune checkpoint inhibitors (ICIs). This study aimed to determine the association between the number of irAEs and clinical outcomes. This was a retrospective study that included patients with lung cancer, melanoma, and head and neck cancer who were treated with anti-programmed cell death (ligand) 1 (PD-1/PD-L1) monotherapy. We evaluated the association between the number of irAEs and progression-free survival (PFS) in the simple Cox regression analysis. To eliminate the immortal-time bias, an additional landmark analysis was performed. In total, 92, 69, and 37 patients were allocated to the no, single, and multisystem irAEs groups, respectively. The multisystem irAEs were associated with better PFS compared to the no irAE group. In contrast, at the 12-week landmark, multisystem irAEs were associated with poor PFS compared to the no irAEs group. Furthermore, the rate of treatment suspension owing to irAEs in the multisystem irAEs group (62.5%) was higher than that in the single irAE group (17.3%) at the 12-week landmark. The incidence of multisystem irAEs was associated with improved clinical outcomes in patients with lung cancer, melanoma, and head and neck cancer treated with PD-1/PD-L1 inhibitor monotherapy. However, these results may be influenced by a potential immortal-time bias. When accounting for this bias, the early development of multisystem irAEs within 12 weeks was linked to treatment suspension and poorer clinical outcomes.

Benmelstobart plus anlotinib in patients with EGFR-positive advanced NSCLC after failure of EGFR TKIs therapy: a phase I/II study

The effect of immune‐based therapies on patients with epidermal growth factor receptor (EGFR)-positive advanced non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitor (TKI) therapy remains unclear. The ALTER-L038 study aimed to evaluate efficacy and safety of a chemotherapy-free combination of benmelstobart, an anti-programmed cell death ligand 1 antibody, and anlotinib, a small-molecule multi-target anti-angiogenic TKI, in EGFR-positive advanced NSCLC patients who progressed after EGFR TKI therapy. Patients were enrolled in a phase I/II study. In phase I (dose-escalation), patients received anlotinib (8, 10, 12 mg) plus benmelstobart (1200 mg). Recommended phase II dose, determined during phase I, was used in phase II dose-expansion cohort. Primary endpoints were maximum tolerable dose in phase I and progression-free survival (PFS) in phase II. At the data cutoff date (March 10, 2024), 55 patients were enrolled in phase II dose-expansion cohort. Median PFS of patients included in phase II cohort was 9.0 months, median overall survival was 28.9 months, objective response rate was 25.5%, disease control rate was 87.3%, and median duration of response was 19.8 months. Incidence of grade ≥3 treatment-related adverse events in study population was 25.5% (14/55), whereas grade ≥3 immune-related adverse events occurred in 10.9% (6/55) of patients. Benmelstobart plus anlotinib showed promising anti-tumor efficacy with tolerable safety profile, supporting the value of further development of this convenient chemotherapy-free regimen for patients with EGFR-positive advanced NSCLC who progressed after EGFR TKI therapy. Trial Registration: ChiCTR1900026273.

Tumour cell-released autophagosomes promote lung metastasis by upregulating PD-L1 expression in pulmonary vascular endothelial cells in breast cancer.

Establishing an immunosuppressive premetastatic niche (PMN) in distant organs is crucial for breast cancer metastasis. Vascular endothelial cells (VECs) act as barriers to transendothelial cell migration. However, the immune functions of PMNs remain unclear. Tumour cell-released autophagosomes (TRAPs) are critical modulators of antitumour immune responses. Herein, we investigated the mechanism through which TRAPs modulate the immune function of pulmonary VECs in lung PMN in breast cancer. Immortalised mouse pulmonary microvascular endothelial cells were incubated with TRAPs in vitro. RNA sequencing, flow cytometry, and western blotting were employed to assess immunosuppressive function and mechanism. In vivo, TRAP-trained and autophagy-deficient tumour mice were used to detect immunosuppression, and high-mobility group box 1 (HMGB1)-deficient TRAP-trained and TLR4 knockout mice were utilised to investigate the underlying mechanisms of pulmonary VECs. Additionally, the efficacy of anti-programmed cell death ligand-1 (PD-L1) immunotherapy was evaluated in early tumour-bearing mice. HMGB1 on TRAPs surfaces stimulated VECs to upregulate PD-L1 via a TLR4-MyD88-p38/STAT3 signalling cascade that depended on the cytoskeletal movement of VECs. Importantly, PD-L1 on TRAP-induced VECs can inhibit T cell function, promote lung PMN immunosuppression, and result in more pronounced lung metastasis. Treatment with anti-PD-L1 reduces lung metastasis in early stage tumour-bearing mice. These findings revealed a novel role and mechanism of TRAP-induced immunosuppression of pulmonary VECs in lung PMN. TRAPs and their surface HMGB1 are important therapeutic targets for reversing immunosuppression, providing a new theoretical basis for the treatment of early stage breast cancer using an anti-PD-L1 antibody.

MerTK+ macrophages promote melanoma progression and immunotherapy resistance through AhR-ALKAL1 activation.

Despite our increasing understanding of macrophage heterogeneity, drivers of macrophage phenotypic and functional polarization in the microenvironment are not fully elucidated. Here, our single-cell RNA sequencing data identify a subpopulation of macrophages expressing high levels of the phagocytic receptor MER proto-oncogene tyrosine kinase (MerTK+ macrophages), which is closely associated with melanoma progression and immunotherapy resistance. Adoptive transfer of the MerTK+ macrophages into recipient mice notably accelerated tumor growth regardless of macrophage depletion. Mechanistic studies further revealed that ALK And LTK Ligand 1 (ALKAL1), a target gene of aryl hydrocarbon receptor (AhR), facilitated MerTK phosphorylation, resulting in heightened phagocytic activity of MerTK+ macrophages and their subsequent polarization toward an immunosuppressive phenotype. Specifically targeted delivery of AhR antagonist to tumor-associated macrophages with mannosylated micelles could suppress MerTK expression and improved the therapeutic efficacy of anti-programmed cell death ligand 1 therapy. Our findings shed light on the regulatory mechanism of MerTK+ macrophages and provide strategies for improving the efficacy of melanoma immunotherapy.

Association of concomitant H1 antihistamine and immune checkpoint inhibitor therapy on survival outcome and safety in patients with advanced primary lung cancer: a cohort study.

Antihistamines alleviate the side effects of antitumor drugs and exert antitumor effects. This study aimed to investigate the potential impact of short-term concomitant use of antihistamines with immune checkpoint inhibitor (ICI) therapy on the efficacy and immune-related adverse events (irAEs) of immunotherapy for patients with advanced lung cancer. We retrospectively analyzed the medical records of 211 patients diagnosed with advanced primary lung cancer and treated with immunotherapy at Tianjin Medical University Cancer Institute and Hospital between January 1, 2018, and January 1, 2022. Among these patients, 109 who received H1 antihistamine during the infusion of anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) antibodies were assigned to the experimental group; meanwhile, the remaining 102 patients who did not receive H1 antihistamines were assigned to the control group. Balancing was achieved through inverse probability of treatment weight (IPTW) estimation. The data were analyzed using Kaplan-Meier curves and Cox regression analyses. The median progression-free survival (mPFS) was 12.7 months in the experimental group and 4.3 months in the control group, while the median overall survival (mOS) was 32.8 months in the experimental group and 18.1 months in the control group. In the experimental group, patients treated with only H1 antihistamines had longer mPFS and mOS compared with those who received H1 plus H2 antihistamines. Similarly, in the control group, patients who did not receive antihistamines had a longer mPFS and mOS than those who only received H2 antihistamines. After conducting multivariate analyses, we found that H1 and H2 antihistamines were respectively identified as good and poor independent prognostic factors for both progression-free survival (PFS) and overall survival (OS). The rates of irAEs in the experimental and control groups were 52.4% and 69.2%, respectively, and grade ≥3 irAEs occurred in 4.5% and 25.9% of patients, respectively. Concomitant use of H1 antihistamines can improve immunotherapy efficacy and reduce irAEs. Meanwhile, concomitant use of H2 antihistamines is associated with reduced PFS and OS time.

Artificial Intelligence-Powered Spatial Analysis of Tumor-Infiltrating Lymphocytes as a Potential Biomarker for Immune Checkpoint Inhibitors in Patients with Biliary Tract Cancer.

Recently, anti-programmed cell death-1/anti-programmed cell death ligand-1 (anti-PD1/L1) immunotherapy has been demonstrated for its efficacy when combined with cytotoxic chemotherapy in randomized phase 3 trials for advanced biliary tract cancer (BTC). However, no biomarker predictive of benefit has been established for anti-PD1/L1 in BTC. Here, we evaluated tumor-infiltrating lymphocytes (TIL) using artificial intelligence-powered immune phenotype (AI-IP) analysis in advanced BTC treated with anti-PD1. Pretreatment hematoxylin and eosin (H&E)-stained whole-slide images from 339 patients with advanced BTC who received anti-PD1 as second-line treatment or beyond, were employed for AI-IP analysis and correlative analysis between AI-IP and efficacy outcomes with anti-PD1. Next, data and images of the BTC cohort from The Cancer Genome Atlas (TCGA) were additionally analyzed to evaluate the transcriptomic and mutational characteristics of various AI-IP in BTC. Overall, AI-IP were classified as inflamed [high intratumoral TIL (iTIL)] in 40 patients (11.8%), immune-excluded (low iTIL and high stromal TIL) in 167 patients (49.3%), and immune-desert (low TIL overall) in 132 patients (38.9%). The inflamed IP group showed a substantially higher overall response rate compared with the noninflamed IP groups (27.5% vs. 7.7%, P < 0.001). Median overall survival and progression-free survival were significantly longer in the inflamed IP group than in the noninflamed IP group (OS, 12.6 vs. 5.1 months; P = 0.002; PFS, 4.5 vs. 1.9 months; P < 0.001). In the TCGA cohort analysis, the inflamed IP showed increased cytolytic activity scores and IFNγ signature compared with the noninflamed IP. AI-IP based on spatial TIL analysis was effective in predicting the efficacy outcomes in patients with BTC treated with anti-PD1 therapy. Further validation is necessary in the context of anti-PD1/L1 plus gemcitabine-cisplatin.

Predictive Biomarkers and Resistance Mechanisms of Checkpoint Inhibitors in Malignant Solid Tumors.

Predictive biomarkers for immune checkpoint inhibitors (ICIs) in solid tumors such as melanoma, hepatocellular carcinoma (HCC), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), endometrial carcinoma, renal cell carcinoma (RCC), or urothelial carcinoma (UC) include programmed cell death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), defective deoxyribonucleic acid (DNA) mismatch repair (dMMR), microsatellite instability (MSI), and the tumor microenvironment (TME). Over the past decade, several types of ICIs, including cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, anti-programmed cell death 1 (PD-1) antibodies, anti-programmed cell death ligand 1 (PD-L1) antibodies, and anti-lymphocyte activation gene-3 (LAG-3) antibodies have been studied and approved by the Food and Drug Administration (FDA), with ongoing research on others. Recent studies highlight the critical role of the gut microbiome in influencing a positive therapeutic response to ICIs, emphasizing the importance of modeling factors that can maintain a healthy microbiome. However, resistance mechanisms can emerge, such as increased expression of alternative immune checkpoints, T-cell immunoglobulin (Ig), mucin domain-containing protein 3 (TIM-3), LAG-3, impaired antigen presentation, and alterations in the TME. This review aims to synthesize the data regarding the interactions between microbiota and immunotherapy (IT). Understanding these mechanisms is essential for optimizing ICI therapy and developing effective combination strategies.

Microfluidic-enabled aptamer-modified liposomal probes for targeted transient triplet differential photoacoustic imaging

Photoacoustic (PA) imaging, merging high spatial resolution and deep tissue penetration, holds promise for biomedical applications, particularly cancer diagnosis. The effectiveness of PA imaging heavily relies on the use of contrast agents that enhance the PA signal. However, the efficient preparation of targeted PA contrast agents remains a challenge. Here, we report the development of microfluidic-enabled aptamer-modified liposomal probes for targeted transient triplet differential (TTD) PA imaging. Utilizing projection micro stereolithography (PµSL) 3D printing, we fabricated cost-effective microfluidic chips for the rapid synthesis of methylene blue (MB)-loaded anti-programmed cell death ligand-1 (anti-PDL1) aptamer-modified liposomes (Apt-MB-Lip). We conducted the TTD-PA imaging of Apt-MB-Lip to improve imaging sensitivity by reducing background noise. In vivo TTD-PA experiments demonstrated the superior targeting ability and sustained presence of the Apt-MB-Lip in tumors. Our findings underscore the potential of these targeted probes for advanced diagnostic and therapeutic applications.

The Impact of Infections in Patients Treated with Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma.

Background: The therapeutic landscape of unresectable hepatocellular carcinoma (uHCC) continues to evolve. Atezolizumab, an anti-programmed cell death ligand 1 (PD-1) immune checkpoint inhibitor (ICI), in combination with bevacizumab, has substantially improved outcomes. This study aims to evaluate the incidence, risk factors, and outcomes in patients who develop infections while receiving atezolizumab and bevacizumab for uHCC. Methods: Patients who received atezolizumab and bevacizumab for uHCC at a single hospital network were included. Types and rates of infections were reported. Covariates compared among infected and non-infected cohorts included age, sex, race, comorbidities, Eastern Cooperative Oncology Group (ECOG) performance status, immunosuppressive use, chronic infections, number of cycles of ICIs given, antibiotic or antiviral therapies at ICI initiation, and line of therapy (first-line, second-line, greater than second-line). Results: Out of 810 evaluable patients, 34 uHCC patients were treated with atezolizumab plus bevacizumab. The mean ± SD age was 66.29 ± 9.39; 28 (82.35%) were males. There were 17 (50%) patients with reported infection, with bacterial infection occurring in 12 (70.59%) patients and COVID-19 in 4 (23.5%). Of the infected patients, eight (47.06%) had one infection, five (29.41%) had two infections, and two (11.76%) had three or more infections. Infected and non-infected patients received a median of 12 (IQR: 5-17) and 4 (IQR: 3-12) ICI cycles (p = 0.18), respectively. Infections did not negatively impact OS or PFS but resulted in treatment delays and discontinuation in 11 (64.71%) and 7 (41.18%) patients, respectively. At the last follow-up, 19 (55.88%) patients died, 9 (52.94%) in the non-infected group vs. 10 (58.82%) in the infected group (p = 1.0). Conclusions: While a broad array of infections occurred in 50% of the patients in this cohort, it did not negatively impact survival outcomes. However, it did impact morbidity, with more all-cause admissions and treatment delays.

Construction and preclinical evaluation of a 124I-labelled bispecific antibody targeting PD-L1 and PD-L2.

NB12 is a bispecific antibody that consists of two anti-programmed cell death-ligand 1 (PD-L1) nanobodies and two anti-programmed cell death-ligand 2 (PD-L2) nanobodies. The aim of this study was to design a novel tracer, [124I]I-NB12, targeting PD-L1/2 and perform preclinical evaluations to dynamically monitor PD-L1/2 expression for determining cancer patient responsiveness to ICI therapy. NB12 was labelled with the radionuclide 124I at room temperature (RT). An in vitro binding assay was performed to assess the affinity of [124I]I-NB12 for PD-L1 and PD-L2. Cellular uptake, pharmacokinetic, and biodistribution experiments were performed to evaluate the biological properties. Micro-PET/CT imaging with [124I]I-NB12 was conducted at different time points. Immunohistochemical and haematoxylin and eosin (HE) staining experiments were carried out using tumour tissues. Routine blood, biochemical indices and major organ pathology were used to evaluate the biosafety of the tracers. The radiochemical yield of [124I]I-NB12 was 84.62 ± 3.90%, and the radiochemical purity (RCP) was greater than 99%. [124I]I-NB12 had a high affinity for the PD-L1 (Kd = 19.82 nM) and PD-L2 (Kd = 2.93 nM). Cellular uptake experiments confirmed that the uptake of [124I]I-NB12 by A549-PDL1/2 cells was greater than that by A549 cells. The half-lives of the distribution phase and elimination phase were 0.26h and 4.08h, respectively. Micro-PET/CT showed significant [124I]I-NB12 uptake in the tumour region of A549-PDL1/2 tumour-bearing mice compared with A549 tumour-bearing mice 24h postinjection. Immunohistochemical and HE staining experiments confirmed that tumour-bearing mice was successfully constructed. We constructed a bispecific antibody that targets PD-L1 and PD-L2, namely, [124I]I-NB12. Biological evaluation revealed its specificity and affinity for PD-L1/2, and micro-PET/CT confirmed the feasibility of visualizing tumour PD-L1/2 in vivo. Using [124I]I-NB12 may be a promising strategy for identifying cancer patients that can potentially benefit from ICI therapy.

Sequential delivery of photosensitizers and checkpoint inhibitors by engineered bacteria for enhanced cancer photodynamic immunotherapy.

Engineered bacteria-based cancer therapy has increasingly been considered to be a promising therapeutic strategy due to the development of synthetic biology. Wherein, engineering bacteria-mediated photodynamic therapy (PDT)-immunotherapyshows greater advantages and potential in treatment efficiency than monotherapy. However, the unsustainable regeneration of photosensitizers (PSs) and weak immune responses limit the therapeutic efficiency. Herein, we developed an engineered bacteria-based delivery system for sequential delivery of PSs and checkpoint inhibitors in cancer PDT-immunotherapy. The biosynthetic pathway of 5-aminolevulinic acid (5-ALA) was introduced into Escherichia coli, yielding a supernatant concentration of 172.19 mg/L after 10 h of growth. And another strain was endowed with the light-controllable releasement of anti-programmed cell death-ligand 1 nanobodies (anti-PD-L1). This system exhibited a collaborative effect, where PDT initiated tumor cell death and the released tumor cell fragments stimulated immunity, followed by the elimination of residual tumor cells. The tumor inhibition rate reached 74.97%, and the portion of activated T cells and inflammatory cytokines were reinforced. The results demonstrated that the engineered bacteria-based collaborative system could sequentially deliver therapeutic substance and checkpoint inhibitors, and achieve good therapeutic therapy. This paper will provide a new perspective for the cancer PDT-immunotherapy.

ALK5/VEGFR2 dual inhibitor TU2218 alone or in combination with immune checkpoint inhibitors enhances immune-mediated antitumor effects

Transforming growth factor β (TGFβ) is present in blood of patients who do not respond to anti-programmed cell death (ligand) 1 [PD-(L)1] treatment, and through synergy with vascular endothelial growth factor (VEGF), it helps to create an environment that promotes tumor immune evasion and immune tolerance. Therefore, simultaneous inhibition of TGFβ/VEGF is more effective than targeting TGFβ alone. In this study, the dual inhibitory mechanism of TU2218 was identified through in vitro analysis mimicking the tumor microenvironment, and its antitumor effects were analyzed using mouse syngeneic tumor models. TU2218 directly restored the activity of damaged cytotoxic T lymphocytes (CTLs) and natural killer cells inhibited by TGFβ and suppressed the activity and viability of regulatory T cells. The inactivation of endothelial cells induced by VEGF stimulation was completely ameliorated by TU2218, an effect not observed with vactosertib, which inhibits only TGFβ signaling. The combination of TU2218 and anti-PD1 therapy had a significantly greater antitumor effect than either drug alone in the poorly immunogenic B16F10 syngeneic tumor model. The mechanism of tumor reduction was confirmed by flow cytometry, which showed upregulated VCAM-1 expression in vascular cells and increased influx of CD8 + CTLs into the tumor. As another strategy, combination of anti-CTLA4 therapy and TU2218 resulted in high complete regression (CR) rates in CT26 and WEHI-164 tumor models. In particular, immunological memory generated by the combination of anti-CTLA4 and TU2218 in the CT26 model prevented the development of tumors after additional tumor cell transplantation, suggesting that the TU2218-based combination has therapeutic potential in immunotherapy.

Targeting Hydrogel for Intelligent Recognition and Spatiotemporal Control in Cell-Based Therapeutics.

Smart drug platforms based on spatiotemporally controlled release and integration of tumor imaging are expected to overcome the inefficiency and uncertainty of traditional theranostic modes. In this study, a composite consisting of a thermosensitive hydrogel (polyvinyl alcohol-carboxylic acid hydrogel (PCF)) and a multifunctional nanoparticle (Fe3O4@Au/Mn(Zn)-4-carboxyphenyl porphyrin/polydopamine (FAMxP))is developed to combine tumor immunogenic cell death (ICD)/immune checkpoint blockade (ICB) therapy under the guidance of magnetic resonance imaging (MRI) and fluorescence imaging (FI). It can not only further recognize the target cells through the folate receptor of tumor cells, but also produce thermal dissolution after exposure to near-infrared light to slowly release FAMxP in situ, thereby prolonging the treatment time and avoiding tumor recurrence. As FAMxP entered the tumor cells, it released FAMx in a pH-dependent manner. Chemodynamic, photothermal and photodynamic therapy can cause significant ICD in cancer cells. ICB can thus be further enhanced by injecting anti-programmed cell death ligand 1, improving the effectiveness of tumor treatment. The developed PCF-FAMxP composite hydrogel may represent an updated drug design approach with simple compositions for cooperative MRI/FI-guided targeted therapeutic pathways for tumors.

Cross-Cancer Type Evaluation of Potential Interstitial Lung Disease Complications of Immune Checkpoint Inhibitors Using JADER.

Interstitial lung disease (ILD) is a serious adverse event caused by the administration of immune checkpoint inhibitors (ICIs). However, only few large-scale studies have explored the association among ICI use, underlying cancer type, and ILD complications. This study aimed to analyze the association between the primary cancer type and ICI-induced ILD in a cross-sectional manner using the Japanese Adverse Drug Event Report (JADER) database. Nivolumab and pembrolizumab (anti-programmed cell death 1 (PD-1) antibodies) and durvalumab, avelumab, and atezolizumab (anti-programmed cell death ligand 1 (PD-L1) antibodies) were included as ICIs in this study. Adverse events were identified based on the preferred terms of Medical Dictionary for Regulatory Activities (MedDRA) version 27.0/J listed in the Standardized MedDRA Queries (SMQ) "interstitial lung disease." The reporting odds ratio was calculated to detect the association between ICI use and ILD complications, and a signal was detected if the lower limit of the 95% confidence interval exceeded 1. In the analysis of all cancer types, a signal was detected for all ICIs except avelumab. An association between ICI and ILD was detected for all cancer types with nivolumab. However, pembrolizumab exhibited a signal only in colorectal cancer. In contrast, anti-PD-L1 antibodies displayed signals in five cancer types, excluding head and neck cancer, which was not reported in JADER. Among these cancer types, atezolizumab exhibited a signal only in breast cancer. The results of this study will help guide the safe use of ICIs based on the underlying cancer type in terms of ILD complications.

PH/glutathione-responsive theranostic nanoprobes for chemoimmunotherapy and magnetic resonance imaging of ovarian cancer cells

The integration of immunotherapy and standard chemotherapy holds great promise for enhanced anticancer effects. In this study, we prepared a pH- and glutathione (GSH)-sensitive manganese-doped mesoporous silicon (MMSNs) based drug delivery system by integrating paclitaxel (PTX) and anti-programmed cell death-ligand 1 antibody (aPD-L1), and encapsulating with polydopamine (PDA) for chemoimmunosynergic treatment of ovarian cancer cells. The nanosystem was degraded in response to the tumor weakly acidic and reductive microenvironment. The Mn2+ produced by degradation can be used as a contrast agent for magnetic resonance (MR) imaging to provide visual exposure to tumor tissue. The released PTX can not only kill tumor cells directly, but also induce immunogenic death (ICD) of tumor cells, which can play a synergistic therapeutic effect with aPD-L1. Therefore, our study is expected to provide a promising strategy for improving the efficacy of cancer immunotherapy and the detection rate of cancer.

Necroptosis-Mediated Synergistic Photodynamic and Glutamine-Metabolic Therapy Enabled by a Biomimetic Targeting Nanosystem for Cholangiocarcinoma.

Targeted delivery of glutamine metabolism inhibitors holds promise for cholangiocarcinoma therapy, yet effective delivery vehicles remain a challenge. This study reports the development of a biomimetic nanosystem, termed R-CM@MSN@BC, integrating mesoporous organosilicon nanoparticles with reactive oxygen species-responsive diselenide bonds for controlled release of the glutamine metabolism inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and the photosensitizer Ce6. Erythrocyte membrane coating, engineered with Arg-Gly-Asp (RGD) peptides, not only enhanced biocompatibility but also improved tumor targeting and tissue penetration. Upon laser irradiation, R-CM@MSN@BC executed both photodynamic and glutamine-metabolic therapies, inducing necroptosis in tumor cells and triggering significant immunogenic cell death. Time-of-flight mass cytometry analysis revealed that R-CM@MSN@BC can remodel the immunosuppressive tumor microenvironment by polarizing M1-type macrophages, reducing infiltration of M2-type and CX3CR1+ macrophages, and decreasing T cell exhaustion, thereby increasing the effectiveness of anti-programmed cell death ligand 1 immunotherapy. This strategy proposed in this study presents a viable and promising approach for the treatment of cholangiocarcinoma.

RPN1: a pan-cancer biomarker and disulfidptosis regulator.

Elevated expression of SLC7A11, in conjunction with glucose deprivation, has revealed disulfidptosis as an emerging cell death modality. However, the prevalence of disulfidptosis across tumor cell lines, irrespective of SLC7A11 levels, remains uncertain. Additionally, deletion of the ribophorin I (RPN1) gene imparts resistance to disulfidptosis, yet the precise mechanism linking RPN1 to disulfidptosis remains elusive. The aim of this study is to determine the mechanism of RPN1-induced disulfidptosis and to determine the possibility of RPN1 as a pan-cancer marker. We hypothesized the widespread occurrence of disulfidptosis in various tumor cells, and proposed that RPN1-mediated disulfidptosis may be executed through cell skeleton breakdown. Experimental validation was conducted via flow cytometry, immunofluorescence, and western blot techniques. Furthermore, given RPN1's status as an emerging cell death marker, we utilized bioinformatics to analyze its expression in tumor tissues, clinical relevance, mechanisms within the tumor microenvironment, and potential for immunotherapy. Conducting experiments on breast cancer (MDA-MB-231) and lung cancer (A549) cell lines under glucose-starved conditions, we found that RPN1 primarily induces cell skeleton breakdown to facilitate disulfidptosis. RPN1 demonstrated robust messenger RNA (mRNA) expression across 16 solid tumors, validated by data from 12 tumor types in the Gene Expression Omnibus (GEO). Across 12 cancer types, RPN1 exhibited significant diagnostic potential, particularly excelling in accuracy for glioblastoma (GBM). Elevated RPN1 expression in tumor tissues was found to correlate with improved overall survival (OS) in certain cancers [diffuse large B-cell lymphoma (DLBC) and thymoma (THYM)] but poorer prognosis in others [adrenocortical carcinoma (ACC), kidney chromophobe (KICH), brain lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), and pancreatic adenocarcinoma (PAAD)]. RPN1 is enriched in immune-related pathways and correlates with immune scores in tumor tissues. In urothelial carcinoma (UCC), RPN1 demonstrates potential in predicting the efficacy of anti-programmed cell death ligand 1 (PD-L1) immune therapy. This study underscores RPN1's role in facilitating disulfidptosis, its broad relevance as a pan-cancer biomarker, and its association with the efficacy of anti-PD-L1 immune therapy.