Long-term outcomes of catheter ablation for ventricular arrhythmias: comparing techniques with and without intracardiac echocardiography - what matters?

BACKGROUND: The increasing use of intracardiac echocardiography (ICE) in the ablation of premature ventricular complexes (PVCs) has raised questions about its true efficacy and safety. METHODS: This retrospective study collected the periprocedural complications and PVC burden post ablation. The risk factors of PVC recurrence was further explored. RESULTS: The study included patients treated without ICE (control group, n = 451) and with ICE (ICE group, n = 155) from May 2019 to July 2022. The ICE group demonstrated significantly lower fluoroscopy times and X-ray doses. There were no major complications in the ICE group, and the difference in the occurrence of periprocedural complications between the groups was not statistically significant (p = 0.072). The long-term success rates were similar for the control and ICE groups (89.6% and 87.1%, respectively). The origin of PVCs was identified as the independent factor for ablation success. CONCLUSIONS: The use of ICE did not confer an advantage with regard to long-term success in PVCs ablation. To thoroughly evaluate the safety and effectiveness of ICE in PVCs ablation, a prospective, multicenter, randomized study is warranted.

Tissue-resident CD69+ CXCR6+ Natural Killer cells with exhausted phenotype accumulate in human non-small cell lung cancer.

Natural killer (NK) cells with tissue-residency features (trNK cells) are a new subpopulation of NK cells, which plays an important role in tissue homeostasis. However, the characteristics of trNK cells in the tumor microenvironment (TME) of human cancers remain unclear. Using multicolor flow cytometry, we investigated the quantity, phenotype, and function of trNK cells in biospecimens freshly resected from 60 non-small cell lung cancer (NSCLC) patients. We successfully identified a new CD69+ CXCR6+ trNK subset with an immunomodulatory-like and exhausted phenotype, specifically accumulated in the TME of NSCLC. In vitro experiments showed that CD69+ CXCR6+ trNK cells more readily secreted IFN-γ and TNF-α spontaneously. Furthermore, the production of IFN-γ and TNF-α by tumor-infiltrating CD69+ CXCR6+ trNK cells was not induced by their reactivation in vitro, which is analogous to T-cell exhaustion. Finally, we demonstrated that the dysfunction of CD69+ CXCR6+ trNK cells could be partly ameliorated by PD-1 and CTLA-4 blockade. In summary, we identified a new dysfunctional CD69+ CXCR6+ trNK cell subset that specifically accumulates in the TME of NSCLC. Our findings suggest that CD69+ CXCR6+ trNK cells are a promising target for immune checkpoint inhibitors in the treatment of NSCLC.

The risk factors of thrombus formation and the effect of catheter ablation on repetitive thrombus formation in patients with atrial fibrillation: a single center retrospective study in China.

BACKGROUND: Atrial fibrillation (AF) predisposes patients to the formation of atrial thrombi. The CHA2DS2-VASc score does not include all risk factors for atrial thrombosis. The present study is designed to explore the influencing factors of thrombus formation in patients with AF and to investigate the effect of catheter ablation (CA) on recurrent thrombosis in patients with a history of intracardiac thrombus. METHODS: (1) This study consisted of 1726 patients that underwent CA, among which 58 patients had a history of intracardiac thrombus prior to CA. The risk factors for thrombus formation were explored by comparing the baseline clinical characteristics of patients with and without atrial thrombus. (2) The left atrial appendage flow velocity (LAAFV) in patients with a history of intracardiac thrombus who were willing to undergo transesophageal echocardiography (TEE) at the latest follow-up were examined, and comparisons of the LAAFV was made before and after CA. RESULTS: The median follow-up period is 13 months. Persistent AF was found to be the only independent risk factor affecting the formation of atrial thrombus among the investigated factors (OR 3.152; 95%CI 1.806-5.500; p < 0.001). Twenty-seven patients agreed to undergo TEE during follow-up, no clinical ischemic stroke events were recorded, no recurrent intracardiac thrombus formation was detected in patients, 15 patients maintained sinus rhythm (55.6%) during follow-up; successful CA significantly increased LAAFV (difference between latest evaluation prior to CA 17.46 ± 14.81 cm/s, p < 0.001). CONCLUSIONS: Persistent AF is the only independent risk factor for thrombus formation. Successful CA may improve the LAAFV and thereby decrease the risk of intracardiac thrombus formation.

Clinical Manifestations, Outcomes, and Mortality Risk Factors of Atrial-Esophageal Fistula: A Systematic Review.

INTRODUCTION: Atrial-esophageal fistula (AEF) is a rare but life-threatening complication of catheter ablation. The clinical presentation and mortality risk factors of AEF have not been fully elucidated. The aim of this study was to systematically review the clinical characteristics and prognosis of AEF. METHODS: PubMed was searched from inception to October 2020 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement protocol. RESULTS: A total of 190 AEF patients were included. The mean age was 59.29 ± 11.67 years, 74.21% occurred in males, and 81.58% underwent radiofrequency ablation. AEF occurred within 30 days after ablation in 80.82% of patients and occurred later in patients presenting with neurological symptoms compared with other symptoms (median of onset time: 27.5 days vs. 16 days, p < 0.001). Clinical presentation included fever (81.58%) and neurological symptoms (80.53%). Chest computed tomography (abnormal rate of 91.24%) was the preferred diagnostic test, followed by magnetic resonance imaging of the brain (abnormal rate of 90.91%). Repeated testing improved diagnostic evaluation sensitivity. Distinctive imaging results included free air in the mediastinum (incidence rate of 81.73%) and air embolism of the brain (incidence rate of 57.53%). The overall mortality was 63.16%, with worse nonsurgical treatment outcomes compared with outcomes of surgical treatment (94.19% vs. 33.71%, p < 0.001). Conservative or stent intervention was an independent risk factor for mortality. Age (adjusted odds ratio, 1.063, p = 0.004), presentation with neurological symptoms (adjusted odds ratio, 5.706, p = 0.017), and presentation with gastrointestinal bleeds (adjusted odds ratio, 3.009, p = 0.045) were also predictors of mortality. CONCLUSIONS: AEF is a fatal ablation complication. AEF can be diagnosed using a combination of a clinical history of ablation, infection, or neurological symptoms and an abnormal chest CT. Our analysis supports that surgical treatment reduces the mortality rate.

The role of alcohol consumption on echocardiographic and electrophysiologic changes in atrial fibrillation.

BACKGROUND: A wealth of evidence suggests that alcohol consumption is a risk factor for atrial fibrillation (AF); however, the mechanisms underlying this association are unclear. This makes it challenging to develop therapeutic strategies in patients with AF attributed to alcohol consumption. PURPOSE: To investigate the echocardiographic and electrophysiologic changes caused by alcohol consumption in patients with AF. METHODS: The study was registered in Chinese Clinical Trial Registry (Registration number ChiCTR2000041575). Data on 134 consecutive non-valvular AF patients who underwent radiofrequency catheter ablation in our center was collected from April 1, 2019 to June 30, 2020. Patients were divided into no-alcohol (72) and alcohol groups [categorized into light (34), moderate (11) and heavy (17) alcohol consumption]. All patients underwent echocardiographic and electrophysiologic examinations for the assessment of left atrial (LA) strain, inter-atrial conduction, intra-atrial conduction, and atrial effective refractory period (ERP). RESULTS: Overall, the mean age was 61 ± 11 years and 87 (65%) were males. Compared with the no-alcohol group, impaired peak LA longitudinal strain, obvious inter-atrial conduction delay and increasing ERP dispersion were observed in the alcohol group. Intra-atrial conduction delay and ERP dispersion increased with increasing amounts of alcohol consumption. CONCLUSION: Alcohol consumption was associated with substantial abnormal echocardiographic and electrophysiologic changes in AF patients. These changes may contribute to the occurrence and progression of AF attributed to alcohol consumption, which may help in the development of new strategies for the prevention and management of AF. However further investigation is required.

CD38 identifies pre-activated CD8+ T cells which can be reinvigorated by anti-PD-1 blockade in human lung cancer.

BACKGROUND: CD38 has been observed expressing in activated T cells, while the features and functions of CD38+ T cells in human NSCLC are still unclear. METHODS: Here we uncovered the correlation between CD38 expression and survival and immune infiltration levels in tumor of NSCLC. Then, we collected samples from 51 NSCLC patients to study the biological feature and response to anti-PD-1 of tumor-infiltrating CD38+ CD8+ T cells in vitro. RESULTS: We found CD38 expression correlated with the survival and immune infiltration levels of NSCLC. It is interesting that CD38+ CD8+ T cells enriched in the tumors expressed higher level of cytotoxic molecule, cytokines and PD-1 than CD38- CD8+ T cells. Moreover, PD-1+ subset in tumor-infiltrating CD38+ CD8+ T cells expressed higher level of activated markers than PD-1+ CD38- CD8+ T cells. Next, we found tumor-infiltrating CD38+ CD8+ T cells expressed higher level of CD103, IFN-γ, TNF-α and perforin than CD38- CD8+ T cells when were reactivated in vitro. Finally, we observed that CD38+ CD8+ T cells isolated from tumors could be reinvigorated by anti-PD-1 in vitro. CONCLUSIONS: Our findings demonstrate that CD38 expression defines a subset of CD8+ T cells enriched in tumors of NSCLC which have paradoxical phenotypes and response to anti-PD-1. Our results suggest a pre-priming of these cells is may exist in tumor and consequentially facilitate it acquiring both anti-tumor potency and exhausted phenotype which can be reinvigorated by PD-1 blockade.

Feasibility and safety of left atrial appendage occlusion guided by procedural fluoroscopy only: A pilot study.

BACKGROUND: Left atrial appendage occlusion (LAAO) is usually performed via the guidance of procedural transesophageal echocardiography (TEE) companied by general anesthesia (GA). OBJECTIVE: To investigate the feasibility and safety of LAAO guided by procedural fluoroscopy only. METHODS: The patients eligible for LAAO were enrolled into the current study and received implantation of either Watchman device or LAmbre device. The procedure was carried out with procedural fluoroscopy only and no companied GA; the position, shape, and leakage of the device were assessed by contrast angiography. TEE was performed after 3-month follow-up to evaluate the thrombosis, and leakage of device. RESULTS: Ninety-seven patients with atrial fibrillation (AF) with either Watchman device (n = 49) or LAmbre device (n = 48) were consecutively enrolled. Watchman device group was of lower CHA2 DS2 -VASc and HAS-BLED scores compared with LAmbre device groups (p < .05); the two groups had similar distributions of other baseline characteristics (p > .05), including procedural success rate (98.0% vs. 97.9%), mean procedure time, mean fluoroscopy time, total radiation dose, contrast medium dose, percentage of peri-device leakage. Pericardial effusions requiring intervention occurred in two of the Watchman group. TEE follow-up found no patient with residual leakage ≥5 mm at 3 months and no device related thrombosis (DRT). During the 22.0 ± 11.1 months follow-up, two patients experienced ischemic stroke. CONCLUSIONS: LAAO with the procedural imaging of fluoroscopy only exhibited the promising results of efficacy and safety. A prospective randomized multicenter study would be required to verify the observations in this study.

A systematic review and meta-analysis to determine the effect of oral anticoagulants on incidence of dementia in patients with atrial fibrillation.

AIMS: To assess the effect of oral anticoagulant (OAC) administration on incidence of dementia in patients with atrial fibrillation (AF) with Systematic review and meta-analysis. METHODS: We systematically searched the electronic databases including Pubmed, Embase, Cochrane library and ClinicalTrails.gov for relevant articles. The primary outcome was the incidence of dementia. The adjusted risk ratio (RR), odds ratio or hazard ratio were extracted and pooled by the random-effects models. Subgroup analysis was performed according to the setting observational window. Risk of bias was assessed using the Newcastle-Ottawa Scale, while publication bias was assessed by the Begg's and Egger's tests. RESULTS: Nine studies were included in this review (2 prospective and 7 retrospective observational studies, including 613,920 patients). The results presented the significant association between OAC therapy and the reduced risk of dementia compared with no treatment (RR [95% CI] = 0.72 [0.60, 0.86], I2  = 97.2%; P = .000). In the subgroup analysis with an observational window, the pooled RR became statistically non-significant (including four studies, RR [95% CI] = 0.75 [0.51, 1.10], I2  = 98.8%; P = .000). There is no significant risk of bias and publication bias. CONCLUSIONS: This study indicated the protective effect of OAC therapy for dementia in patients with AF. However, the results are limited because of high heterogeneity, inconsistent direction of effect in subgroup analysis with an observational window. Further prospective well-designed study is needed with longer follow-up duration in younger patients.

Is Epicardial Adipose Tissue Associated with Atrial Fibrillation Following Cardiac Surgery? A Systematic Review and Meta-Analysis.

BACKGROUND: Although epicardial adipose tissue (EAT) has been proven to be related to atrial fibrillation (AF) and post-ablation AF recurrence, the association between EAT and AF after cardiac surgery (AFACS) remains unclear. OBJECTIVE: This study was a systematic review and meta-analysis that assessed the relationship between EAT and AFACS. METHODS: Electronic databases were systematically searched for "atrial fibrillation" and "epicardial adipose tissue." The analysis was stratified according to the EAT measurement into three meta-analyses as (1) total EAT volume, (2) left atrial (LA)-EAT volume, and (3) EAT thickness. Standardized mean difference (SMD) was estimated using a random effects model. RESULTS: Eight articles with 10 studies (546 patients) were included. The meta-analysis revealed that EAT was higher in those with AFACS irrespective of the EAT measurement (total EAT volume: SMD = 0.56 mL, 95% confidence interval, CI = 0.56-1.10 mL, I2 = 0.90, P = .04; EAT thickness: SMD = 0.85 mm, 95% CI = 0.04-1.65 mm, I2 = 0.90, P = .04; LA-EAT volume: SMD = 0.57 mL, 95% CI = 0.23-0.92 mL, I2 = 0.00, P = .001). CONCLUSION: EAT was higher in patients with AFACS, measured either as volume or thickness.

Label-Free Impedimetric Immunosensors Modulated by Protein A/Bovine Serum Albumin Layer for Ultrasensitive Detection of Salbutamol.

The sensing properties of immunosensors are determined not only by the amount of immobilized antibodies but also by the number of effective antigen-binding sites of the immobilized antibody. Protein A (PA) exhibits a high degree of affinity with the Fc part of IgG antibody to feasibly produce oriented antibody immobilization. This work proposes a simple method to control the PA surface density on gold nanostructure (AuNS)-deposited screen-printed carbon electrodes (SPCEs) by mixing concentration-varied PA and bovine serum albumin (BSA), and to explore the effect of PA density on the affinity attachment of anti-salbutamol (SAL) antibodies by electrochemical impedance spectroscopy. A concentration of 100 µg/mL PA and 100 µg/mL BSA can obtain a saturated coverage on the 3-mercaptoproponic acid (MPA)/AuNS/SPCEs and exhibit a 50% PA density to adsorb the amount of anti-SAL, more than other concentration-varied PA/BSA-modified electrodes. Compared with the randomly immobilized anti-SAL/MPA/AuNS/SPCEs and the anti-SAL/PA(100 µg/mL):BSA(0 µg/mL)/MPA/AuNS/SPCE, the anti-SAL/PA(100 µg/mL): BSA(100 µg/mL)/MPA/AuNS/SPCE-based immunosensors have better sensing properties for SAL detection, with an extremely low detection limit of 0.2 fg/mL and high reproducibility (<2.5% relative standard deviation). The mixture of PA(100 µg/mL):BSA(100 µg/mL) for the modification of AuNS/SPCEs has great promise for forming an optimal protein layer for the oriented adsorption of IgG antibodies to construct ultrasensitive SAL immunosensors.

Successful catheter ablation of atrial fibrillation improves but not reverses the abnormalities of left atrial mechanics and energy loss.

BACKGROUND: Dissipative energy loss (EL), a new index to quantify the inefficient blood flow, has not been explored within left atrium (LA) in patients with atrial fibrillation (AF). We aimed to study the intra-atrial flow and mechanics in patients with AF before and after successful catheter ablation by evaluating EL and LA global longitudinal strain (LAS). METHODS: In our study, there were 53 patients undergoing catheter ablation for AF at baseline (AF group) and 33 age- and sex-matched controls. They were both assessed of LA EL using vector flow mapping (VFM) and of LAS using two-dimensional tracking (2DTT) during systole (sys), early diastole (ed), and atrial contraction phase (ac). Out of 53 patients, 37 patients who sustained sinus rhythm and carried out the echocardiographic examination at 3 and 6 months follow-up were evaluated of change in EL and LAS. The independent predictors of EL during three phases in AF group were performed using stepwise multivariate linear regression analyses. RESULTS: Left atrium EL and LAS among all phases in AF group were significantly lower than controls (all P < 0.01). During follow-up, LASsys and LASac both significantly improved at 3 and 6 months (both P < 0.01), and ELac significantly increased after 6 months (P < 0.05); ELsys, ELed and LASed were no significant change; EL and LAS among all phases were no normalized during follow-up. The independent predictors of EL were: for ELsys, BSA (P = 0.004) and LASac (P = 0.025); for ELed, E (P = 0.001) and A (P = 0.014); for ELac, E/A (P < 0.001). CONCLUSION: Vector flow mapping and 2DTT revealed impaired intra-atrial flow and mechanics. Successful catheter ablation for AF slightly improves but not reverses the aforementioned impairment, indicating the continuous LA dysfunction.

Effect of Poly-l-Lysine Polycation on the Glucose Oxidase/Ferricyanide Composite-Based Second-Generation Blood Glucose Sensors.

Second-generation glucose biosensors are presently the mainstream commercial solution for blood glucose measurement of diabetic patients. Screen-printed carbon electrodes (SPCEs) are the most-used substrate for glucose testing strips. This study adopted hydrophilic and positively charged α-poly-l-lysine (αPLL) as the entrapment matrix for the immobilization of negatively charged glucose oxidase (GOx) and ferricyanide (FIC) on SPCEs to construct a disposable second-generation glucose biosensor. The αPLL modification is shown to facilitate the redox kinetics of FIC and ferrocyanide on the SPCEs. The SPCEs coated with 0.5 mM GOx, 99.5 mM FIC, and 5 mM αPLL had better sensitivity for glucose detection due to the appreciable effect of protonated αPLL on the promotion of electron transfer between GOx and FIC. Moreover, the SPCEs coated with 0.5 mM GOx, 99.5 mM FIC, and 5 mM αPLL were packaged as blood glucose testing strips for the measurement of glucose-containing human serum samples. The glucose testing strips had good linearity from 2.8 mM to 27.5 mM and a detection limit of 2.3 mM. Moreover, the 5 mM αPLL-based glucose testing strips had good long-term stability to maintain GOx activity in aging tests at 50 °C.

TWEAK/Fn14 mediates atrial-derived HL-1 myocytes hypertrophy via JAK2/STAT3 signalling pathway.

Atrial myocyte hypertrophy is one of the most important substrates in the development of atrial fibrillation (AF). The TWEAK/Fn14 axis is a positive regulator of cardiac hypertrophy in cardiomyopathy. This study therefore investigated the effects of Fn14 on atrial hypertrophy and underlying cellular mechanisms using HL-1 atrial myocytes. In patients with AF, Fn14 protein levels were higher in atrial myocytes from atrial appendages, and expression of TWEAK was increased in peripheral blood mononuclear cells, while TWEAK serum levels were decreased. In vitro, Fn14 expression was up-regulated in response to TWEAK treatment in HL-1 atrial myocytes. TWEAK increased the expression of ANP and Troponin T, and Fn14 knockdown counteracted the effect. Inhibition of JAK2, STAT3 by specific siRNA attenuated TWEAK-induced HL-1 atrial myocytes hypertrophy. In conclusion, TWEAK/Fn14 axis mediates HL-1 atrial myocytes hypertrophy partly through activation of the JAK2/STAT3 pathway.

Interaction between nitric oxide signaling and gap junctions during ischemic preconditioning: Importance of S-nitrosylation vs. protein kinase G activation.

Much effort has been dedicated to exploring the mechanisms of IPC, and the GJ is one of the proposed targets of IPC. Several lines of evidence have indicated that NO affects GJ permeability regulation and expression of connexin isoforms. NO-induced stimulation of the sGC-cGMP pathway and the subsequent PKG activation could lead directly to connexin phosphorylation and GJ coupling modification. Additionally, because NO-induced cardioprotection against I/R injury beyond the cGMP/PKG-dependent pathway has been reported in isolated cardiomyocytes, it has been posited that NO-mediated GJ coupling might be independent from the activation of the NO-induced cGMP/PKG pathway during IPC. S-nitrosylation by NO exerts a major influence in IPC-induced cardioprotection. It has been suggested that NO-mediated cardioprotection during IPC was not dependent on sGC/cGMP/PKG but on SNO signaling. We need more researches to prove that which signaling pathway (S-nitrosylation or protein kinase G activation) is the major one modulating GJ coupling during IPC. The aim of review article is to discuss the possible signaling pathways of NO in regulating GJ during IPC.

Drug-induced AF: Arrhythmogenic Mechanisms and Management Strategies.

AF is a prevalent condition that is associated with various modifiable and unmodifiable risk factors. Drug-induced AF, despite being commonly under-recognised, can be relatively easy to manage. Numerous cardiovascular and non-cardiovascular agents, including catecholaminergic agents, adenosine, anti-tumour agents and others, have been reported to induce AF. However, the mechanisms underlying drug-induced AF are diverse and not fully understood. The complexity of clinical scenarios and insufficient knowledge regarding drug-induced AF have rendered the management of this condition complicated, and current treatment guidelines follow those for other types of AF. Here, we present a review of the epidemiology of drug-induced AF and highlight a range of drugs that can induce or exacerbate AF, along with their molecular and electrophysiological mechanisms. Given the inadequate evidence and lack of attention, further research is crucial to underscore the clinical significance of drug-induced AF, clarify the underlying mechanisms and develop effective treatment strategies for the condition.

Radiofrequency catheter ablation for re-do procedure after single-shot pulmonary vein isolation with pulsed field ablation for paroxysmal atrial fibrillation: case report.

Background: Catheter ablation is frequently used to manage recurrent atrial fibrillation (AF) resistant to drug therapy, with pulmonary vein isolation (PVI) as a key tactic. Pulsed field ablation (PFA) has emerged as an innovative technology for PVI but poses challenges for redo procedures. Case presentation: We report on a 73-year-old female patient who experienced recurrent AF after initial successful PVI using a novel PFA technology and subsequently underwent radiofrequency catheter ablation during a repeat intervention. The reconnection of pulmonary veins was discovered primarily in the anterior region of the right superior PV and the superior portion of the left superior PV. An anatomically-based segmental approach and larger circumferential PVI, followed by additional linear ablations at non-PV trigger sites, proved decisive in preventing further recurrence of atrial tachycardia. Conclusion: While PFA exhibits promise as a secure and efficient modality for PVI, it necessitates excellent contact quality to ensure lasting results. For patients experiencing AF recurrences post-PFI, expanded strategies incorporating both comprehensive PVI and linear ablations at targeted non-PV sites might enhance treatment outcomes.

JAML promotes the antitumor role of tumor-resident CD8+ T cells by facilitating their innate-like function in human lung cancer.

Tissue-resident memory CD8+T cells (CD8+TRMs) are thought to play a crucial role in cancer immunosurveillance. However, the characteristics of CD8+TRMs in the tumor microenvironment (TME) of human non-small cell lung cancer (NSCLC) remain unclear. Here, we report that CD8+TRMs accumulate explicitly and exhibit a unique gene expression profile in the TME of NSCLC. Interestingly, these tumor-associated CD8+TRMs uniquely exhibit an innate-like phenotype. Importantly, we found that junction adhesion molecule-like (JAML) provides an alternative costimulatory signal to activate tumor-associated CD8+TRMs via combination with cancer cell-derived CXADR (CXADR Ig-like cell adhesion molecule). Furthermore, we demonstrated that activating JAML could promote the expression of TLR1/2 on CD8+TRMs, inhibit tumor progression and prolong the survival of tumor-bearing mice. Finally, we found that higher CD8+TRMs and JAML expression in the TME could predict favorable clinical outcomes in NSCLC patients. Our study reveals an intrinsic bias of CD8+TRMs for receiving the tumor-derived costimulatory signal in the TME, which sustains their innate-like function and antitumor role. These findings will shed more light on the biology of CD8+TRMs and aid in the development of potential targeted treatment strategies for NSCLC.

Inflammatory dendritic cells restrain CD11b+CD4+ CTLs via CD200R in human NSCLC.

CD4+ cytotoxic T lymphocytes (CD4+ CTLs) are suggested to play a crucial role in inflammatory diseases, including cancer, but their characteristics in human non-small cell lung cancer (NSCLC) remain unknown. Here, using the cell surface marker CD11b, we identify CD11b+CD4+ CTLs as a cytotoxic subset of CD4+ T cells in multiple tissues of NSCLC patients. In addition, tumor-infiltrating CD11b+CD4+ CTLs show a dysfunctional phenotype with elevated expression of CD200 receptor (CD200R), a negatively immunomodulatory receptor. CD4+ regulatory T (Treg) cells restrain the anti-tumor role of CD11b+CD4+ CTLs via CD200. Mechanistically, inflammatory dendritic cells promote the CD200R expression of CD11b+CD4+ CTLs by secreting interleukin-1ß (IL-1ß). Finally, we demonstrate that CD200 blockade can revive the tumor-killing role of CD11b+CD4+ CTLs and prolong the survival of tumor-bearing mice. Taken together, our study identifies CD11b+CD4+ CTLs in NSCLC with decreased cytotoxicity that can be reinvigorated by CD200 blockade, suggesting that targeting CD200 is a promising immunotherapy strategy in NSCLC.

Epithelium/imcDC2 axis facilitates the resistance of neoadjuvant anti-PD-1 in human NSCLC.

BACKGROUND: Therapeutic resistance is a main obstacle to achieve long-term benefits from immune checkpoint inhibitors. The underlying mechanism of neoadjuvant anti-PD-1 resistance remains unclear. METHODS: Multi-omics analysis, including mass cytometry, single-cell RNA-seq, bulk RNA-seq, and polychromatic flow cytometry, was conducted using the resected tumor samples in a cohort of non-small cell lung cancer (NSCLC) patients received neoadjuvant anti-PD-1 therapy. Tumor and paired lung samples acquired from treatment-naïve patients were used as a control. In vitro experiments were conducted using primary cells isolated from fresh tissues and lung cancer cell lines. A Lewis-bearing mouse model was used in the in vivo experiment. RESULTS: The quantity, differentiation status, and clonal expansion of tissue-resident memory CD8+ T cells (CD8+ TRMs) are positively correlated with therapeutic efficacy of neoadjuvant anti-PD-1 therapy in human NSCLC. In contrast, the quantity of immature CD1c+ classical type 2 dendritic cells (imcDC2) and galectin-9+ cancer cells is negatively correlated with therapeutic efficacy. An epithelium/imDC2 suppressive axis that restrains the antitumor response of CD8+ TRMs via galectin-9/TIM-3 was uncovered. The expression level of CD8+ TRMs and galectin-9+ cancer cell-related genes predict the clinical outcome of anti-PD-1 neoadjuvant therapy in human NSCLC patients. Finally, blockade of TIM-3 and PD-1 could improve the survival of tumor-bearing mouse by promoting the antigen presentation of imcDC2 and CD8+ TRMs-mediated tumor-killing. CONCLUSION: Galectin-9 expressing tumor cells sustained the primary resistance of neoadjuvant anti-PD-1 therapy in NSCLC through galectin-9/TIM-3-mediated suppression of imcDC2 and CD8+ TRMs. Supplement of anti-TIM-3 could break the epithelium/imcDC2/CD8+ TRMs suppressive loop to overcome anti-PD-1 resistance. TRIAL REGISTRATION NUMBER: NCT03732664.

PABPC1L Induces IDO1 to Promote Tryptophan Metabolism and Immune Suppression in Renal Cell Carcinoma.

The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance despite having extensive T-cell infiltration. Elucidation of the mechanisms underlying immune evasion could help identify therapeutic strategies to boost the efficacy of immune checkpoint blockade (ICB) in RCC. This study uncovered a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine 2,3-dioxygenase 1 (IDO1), a prospective target for immunotherapy. PABPC1L was markedly upregulated in RCC, and high PABPC1L expression correlated with unfavorable prognosis and resistance to ICB. PABPC1L bolstered tryptophan metabolism by upregulating IDO1, inducing T-cell dysfunction and Treg infiltration. PABPC1L enhanced the stability of JAK2 mRNA, leading to increased JAK2-STAT1 signaling that induced IDO1 expression. Additionally, PABPC1L-induced activation of the JAK2-STAT1 axis created a positive feedback loop to promote PABPC1L transcription. Conversely, loss of PABPC1L diminished IDO1 expression, mitigated cytotoxic T-cell suppression, and enhanced responsiveness to anti-PD-1 therapy in patient-derived xenograft models. These findings reveal the crucial role of PABPC1L in facilitating immune evasion in RCC and indicate that inhibiting PABPC1L could be a potential immunotherapeutic approach in combination with ICB to improve patient outcomes. SIGNIFICANCE: PABPC1L functions as a key factor in renal cell carcinoma immune evasion, enhancing IDO1 and impeding T-cell function, and represents a potential target to enhance the efficacy of immune checkpoint blockade therapy.