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Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, highly resistant to standard chemotherapy and immunotherapy. Regulatory T cells (Tregs) expressing tumor necrosis factor α receptor 2 (TNFR2) contribute to immunosuppression in PDAC. Treg infiltration correlates with poor survival and tumor progression in patients with PDAC. We hypothesized that TNFR2 inhibition using a blocking monoclonal antibody (mAb) could shift the Treg-effector T cell balance in PDAC, thus enhancing antitumoral responses., Method: To support this hypothesis, we first described TNFR2 expression in a cohort of 24 patients with PDAC from publicly available single-cell analysis data. In orthotopic and immunocompetent mouse models of PDAC, we also described the immune environment of PDAC after immune cell sorting and single-cell analysis. The modifications of the immune environment before and after anti-TNFR2 mAb treatment were evaluated as well as the effect on tumor progression., Results: Patients with PDAC exhibited elevated TNFR2 expression in Treg, myeloid cells and endothelial cells and lower level in tumor cells. By flow cytometry and single-cell RNA-seq analysis, we identified two Treg populations in orthotopic mouse models: Resting and activated Tregs. The anti-TNFR2 mAb selectively targeted activated tumor-infiltrating Tregs, reducing T cell exhaustion markers in CD8 + T cells. However, anti-TNFR2 treatment alone had limited efficacy in activating CD8 + T cells and only slightly reduced the tumor growth. The combination of the anti-TNFR2 mAb with agonistic anti-CD40 mAb promoted stronger T cell activation, tumor growth inhibition, and improved survival and immunological memory in PDAC-bearing mice., Conclusion: Our data suggest that combining a CD40 agonist with a TNFR2 antagonist represents a promising therapeutic strategy for patients with PDAC., Competing Interests: Competing interests: EP is co-founder and consultant for Egle-Tx., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Semaphorin-plexin signaling plays a major role in the tumor microenvironment (TME). In particular, Semaphorin 4D (SEMA4D) has been shown to promote tumor growth and metastasis; however, the role of its high-affinity receptor Plexin-B1 (PLXNB1), which is expressed in the TME, is poorly understood. In this study, we directly targeted PLXNB1 in the TME of triple-negative murine breast carcinoma to elucidate its relevance in cancer progression. We found that primary tumor growth and metastatic dissemination were strongly reduced in PLXNB1-deficient mice, which showed longer survival. PLXNB1 loss in the TME induced a switch in the polarization of tumor-associated macrophages (TAM) toward a pro-inflammatory M1 phenotype and enhanced the infiltration of CD8+ T lymphocytes both in primary tumors and in distant metastases. Moreover, PLXNB1 deficiency promoted a shift in the Th1/Th2 balance of the T-cell population and an antitumor gene signature, with the upregulation of Icos, Perforin-1, Stat3, and Ccl5 in tumor-infiltrating lymphocytes (TILs). We thus tested the translational relevance of TME reprogramming driven by PLXNB1 inactivation for responsiveness to immunotherapy. Indeed, in the absence of PLXNB1, the efficacy of anti-PD-1 blockade was strongly enhanced, efficiently reducing tumor growth and distant metastasis. Consistent with this, pharmacological PLXNB1 blockade by systemic treatment with a specific inhibitor significantly hampered breast cancer growth and enhanced the antitumor activity of the anti-PD-1 treatment in a preclinical model. Altogether, these data indicate that PLXNB1 signaling controls the antitumor immune response in the TME and highlight this receptor as a promising immune therapeutic target for metastatic breast cancers., (©2024 The Authors; Published by the American Association for Cancer Research.)

Objectives: Ascending aorta (AA) dilatation in patients with bicuspid aortic valve (AV) is related both to genetic and haemodynamic factors. The aim of this study is to compare late progression of AA dilatation in bicuspid AV patients undergoing surgical aortic valve replacement (SAVR) versus transcatheter aortic valve implantation (TAVI)., Methods: Data of 189 consecutive patients who underwent AV replacement for severe bicuspid AV stenosis were prospectively collected. Patients who underwent SAVR were compared to patients who underwent TAVI. Indication to the procedure was validated by the institutional Heart Team. Aortic diameters were evaluated by transthoracic echocardiogram. Differences between preoperative and long-term follow-up AA diameters were compared in the 2 groups., Results: Between January 2015 and December 2021, 143 (76%) patients underwent SAVR and 46 (24%) patients underwent TAVI. At 4.6 (standard deviation 1.7) years follow-up, patients in the TAVI group showed significantly lower survival (P = 0.00013) and event-free survival (P < 0.0001). AA diameter progression was lower in surgical compared to transcatheter patients, 0.95 (0.60, 1.30) vs 1.65 (0.67, 2.63) mm, P = 0.02. AA diameter progression indexed for body surface area and height was lower in the surgical group: 0.72 (0.38, 1.05) vs 1.05 (0.39, 1.71) mm/m2, P = 0.02, and 0.59 (0.36, 0.81) vs 1.11 (0.44, 1.78) mm/m, P = 0.001, respectively. At multivariable linear regression analysis transcatheter procedure, baseline aortic diameter and paravalvular leak were significantly associated with increased postoperative AA dilatation., Conclusions: Bicuspid AV patients who underwent SAVR, showed significantly less long-term AA diameter progression than patients who underwent transcatheter procedure., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumor distribution of fenretinide, a synthetic retinoid chemically related to all-trans-retinoic acid, after administration of a novel oral nanoformulation of fenretinide, called bionanofenretinide (BNF). BNF was developed to overcome the major limitation of fenretinide: its poor aqueous solubility and bioavailability due to its hydrophobic nature. The method proved to be reproducible, precise and highly accurate for the measurement of the drug and the main metabolites. The lower limit of quantification resulted in 1 ng/mL. The curve range of 1-500 ng/mL and 50-2000 ng/mL, for plasma and tumor homogenate, respectively, was appropriate for the analysis, as demonstrated by the accuracy of between 96.8% and 102.4% for plasma and 96.6 to 102.3% for the tumor. The interdays precision and accuracy determined on quality controls at three different levels were in the ranges of 6.9 to 7.5% and 99.3 to 101.0%, and 0.96 to 1.91% and 102.3 to 105.8% for plasma and tumor, respectively. With the application of the novel assay in explorative pharmacokinetic studies, following acute and chronic oral administration of the nanoformulation, fenretinide was detected in plasma and tumor tissue at a concentration higher than the IC50 value necessary for in vitro inhibitory activity (i.e., 1-5 µM) in different cancer cells lines. We were also able to detect the presence in plasma and tumor of active and inactive metabolites of fenretinide.

Purpose: This systematic review aims to investigate the complication rate of endoscopic spine surgeries, stratifying them by technique, district and kind of procedure performed., Methods: This study was conducted according to the PRISMA statement. The literature search was conducted in MEDLINE, CINAHL, EMBASE, Cochrane Register, OTseeker and ScienceDirect database. Types of studies included were observational studies (cohort studies, case-control studies and case series) and randomised or quasi-randomised clinical with human subjects. No restrictions on publication year were applied. Repeated articles, reviews, expert's comments, congress abstracts, technical notes and articles not in English were excluded. Several data were extracted from the articles. In particular, data of perioperative (≤ 3 months) and late (> 3 months) complications were collected and grouped according to: (1) surgical technique [uniportal full-endoscopic spine surgery (UESS) or unilateral biportal endoscopic spine surgery (UBESS)]; (2) spinal district treated [cervical, thoracic or lumbar] and (3) type of procedure [discectomy/decompression or fusion]. Complication analysis was performed in subgroups with at least 100 patients to have clinically meaningful statistical validity., Results: A total of 117 full-text articles were assessed for eligibility. Of the 117 records included, 95 focused their research on UESS (14 LOE V, 33 LOE IV, 43 LOE III and five LOE II) and 23 on UBESS (three LOE V, eight LOE IV, 10 LOE III and two LOE II). A total of 20,020 patients were extracted to investigate the incidence of different perioperative and late complications, 10,405 for UESS and 9615 for UBESS., Conclusion: The present study summarises the complications reported in the literature for spinal endoscopic procedures. On the one hand, the most relevant described were perioperative complications (transient neurological deficit, dural tear and dysesthesia) that are especially meaningful for endoscopic discectomy and decompression. On the other hand, late complications, such as mechanical implant failure, are more common in endoscopic interbody fusion., Level of Evidence: I., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Addressing facial palsy (FP) presents intricate challenges in achieving natural expressions. Although free functional muscle transfers (FFMT) offer effective smile restoration, age impacts their efficacy. The optimal FFMT age range of 5-55 years is limited by physical fitness, which extends beyond age boundaries. Unilateral FP demands vary; younger patients require dynamic solutions like FFMT, whereas older individuals prioritize public appearance due to baseline distortion. The aim of this study is to describe and to assess a new static technique combining deep plane facelift and fascia lata graft for FP treatment. We conducted a prospective pilot study enrolling unilateral FP patients aged >55 and declining FFMT. Exclusions encompassed prior FP surgery, recent injections, uncontrolled diabetes cognitive deficits, and patients unable to quit smoking. To evaluate this technique, the Glasgow Benefit Inventory (GBI), along with two objective scales, the Face- and Neck-Lift Objective Photo-Numerical Assessment Scale and the eFACE scale, were used. Interrater reliability and intrarater reliability were assessed. Fifteen patients (mean age: 60.9 years) underwent the procedure. Both static and dynamic symmetry significantly improved (p < 0.05), including check volume and position, oral commissure, and jawline. Notably, eye closure enhancement was observed. GBI scores also significantly increased (p < 0.05). Interrater reliability and intrarater reliability were minimal (p = 0.12 and p = 0.13). This combined approach offers a static FP treatment option, especially for the elderly or FFMT-ineligible patients. The relatively brief procedure yields immediate and satisfactory results, suggesting its potential value in FP management. Further comprehensive studies are encouraged to validate the technique's long-term efficacy and applicability across larger populations., (Copyright © 2023 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Aims: The functional capacity of the immune cells is strongly dependent on their metabolic state and inflammatory responses are characterized by a greater use of glucose in immune cells. This study is aimed to establish the role of glucose metabolism and its players [glucose transporter 1 (GLUT-1) and pyruvate kinase isozyme M2 (PKM2)] in the dysregulation of adaptive immunity and inflammation observed in patients with non-ST-segment elevation myocardial infarction (NSTEMI)., Methods and Results: We enrolled 248 patients allocated to three groups: NSTEMI patients, chronic coronary syndromes (CCS) patients, healthy subjects (HSs). NSTEMI patients showed higher expression of GLUT-1 and an enhanced glucose uptake in T cells when compared with CCS patients (P < 0.0001; P = 0.0101, respectively) and HSs (P = 0.0071; P = 0.0122, respectively). PKM2 had a prevalent nuclear localization in T lymphocytes in NSTEMI (P = 0.0005 for nuclear vs. cytoplasm localization), while in CCS and HS, it was equally distributed in both compartments. In addition, the nuclear fraction of PKM2 was significantly higher in NSTEMI compared with HS (P = 0.0023). In NSTEMI patients, treatment with Shikonin and Fasentin, which inhibits PKM2 enzyme activity and GLUT-1-mediated glucose internalization, respectively, led to a significant reduction in GLUT-1 expression along with the down-regulation of pro-inflammatory cytokine expression., Conclusion: NSTEMI patients exhibit dysregulation of the GLUT-1/PKM2 metabolic loop characterized by nuclear translocation of PKM2, where it acts as a transcription regulator of pro-inflammatory genes. This detrimental loop might represent a new therapeutic target for personalized medicine., Competing Interests: Conflict of interest: F.Cr. reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work. G.L. received grant support (to the institution) for investigator-initiated research from American Heart Association, Italian National Health Service, and Italian Minister of Education, University and Research. She is currently involved in the Research Programs of the Italian Cardiovascular Network. She received personal fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Sanofi, and Novartis, outside the submitted work., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To investigate the role of depressive symptoms on clinical outcomes in patients undergoing spinal surgery up to 2-year follow-up., Methods: The study used data from an institutional spine surgery registry (January 2016, through March 2022) to identify patients (> 18 years) undergoing spine surgery. Patients with Oswestry Disability Index (ODI) < 20/100 at baseline or undergoing surgery on the cervical spine or for idiopathic spinal deformity and trauma patients were excluded. The patients were divided into two groups based on the pre-operative Mental Component Summary (MCS) score of the SF-36: depression group (MCS ≤ 35) or non-depression group (MCS > 35). The ODI and MCS scores trajectory were wined over the 24-month post-surgery between groups. Additionally, a secondary subgroup analysis was conducted comparing outcomes between those with depressive symptoms (persistent-depression subgroup) and those without depressive symptoms (never-depression subgroup) at 3 months after surgery., Results: A total of 2164 patients who underwent spine surgery were included. The pre-operative depression group reported higher ODI total scores and lower MCS than the pre-operative non-depression group at all time points (P < 0.001). The persistent-depression subgroup reported higher ODI total scores and lower MCS than the never-depression subgroup at all follow-ups (P < 0.001)., Conclusion: Functional disability and mental health status improve in patients with depression symptoms undergoing spinal surgery. Despite this improvement, they do not reach the values of non-depressed subjects. Over the 2-year follow-up time, patients with depression show a different trajectory of ODI and MCS. Caregivers should be aware of these results to counsel patients with depression symptoms., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Gut microbiota is an emerging editable cardiovascular risk factor. We aim to investigate gut and coronary plaque microbiota, using fecal samples and angioplasty balloons from patients with acute coronary syndrome (ACS), chronic coronary syndrome (CCS) and control subjects. We examined bacterial communities in gut and coronary plaques by 16S rRNA sequencing and we performed droplet digital PCR analysis to investigate the gut relative abundance of the bacterial genes CutC/CntA involved in trimethylamine N-oxide synthesis. Linear discriminant analysis effect size (LEfSe) at the genus and species levels displayed gut enrichment in Streptococcus, Granulicatella and P. distasonis in ACS compared with CCS and controls; Roseburia, C. aerofaciens and F. prausnitzii were more abundant in controls than in patients. Principal component analysis (PCA) of 41 differentially abundant gut taxa showed a clustering of the three groups. In coronary plaque, LEfSe at the genus level revealed an enrichment of Staphylococcus and Streptococcus in ACS, and Paracoccus in CCS, whereas PCA of 15 differentially abundant plaque taxa exhibited clustering of ACS and CCS patients. CutC and CntA genes were more abundant in ACS and CCS than in controls while no significant difference emerged between ACS and CCS. Our results indicate that ACS and CCS exhibit a different gut and plaque microbial signature, suggesting a possible role of these microbiotas in coronary plaque instability., (© 2023. Springer Nature Limited.)

Hemorrhagic complications arising from ventricular drainage procedures are typically asymptomatic and of low volume. A particular subset of these complications, known as delayed intracranial hemorrhage (DICH), is however recognized for its particularly poor prognosis. We primarily aimed to identify epidemiological characteristics associated with DICH, to shed light on its occurrence and potential risk factors. To do so, we performed a retrospective analysis of a series of ten patients who presented with DICH in the context of a ruptured brain arteriovenous malformation (bAVM) and a systematic literature review of all DICH cases reported in the literature. Our ten patients showed delayed neurological deterioration after a ventriculoperitoneal shunt (VPS) procedure, with a computed tomography (CT) scan revealing a DICH surrounding the ventricular catheter, distinct and away from the nidus of their previously ruptured bAVM. Four patients (40%) rapidly declined and passed away, three (30%) required surgical management and the remaining three (30%) demonstrated gradual clinical improvement with conservative management. In the literature, most patients presenting with DICH had hydrocephalus associated with neurovascular disorders (47% of cases), such as bAVM rupture in our present series. These constatations point out the significance of the underlying pathologies potentially being predisposed to these unusual complications.

Abstract: Spinal disorders are the main reasons for sick leave and early retirement among the working population in industrialized countries. When "red flags" are present, spine surgery is the treatment of choice. However, the role of psychosocial factors such as fear-avoidance beliefs in spine surgery outcomes is still debated. The study aims to investigate whether patients presenting high or low levels of fear-avoidance thoughts before the spine surgery reported different surgical results and return-to-work rates over 2 years. From an institutional spine surgery registry, workers surgically treated with a preoperative score in the Oswestry Disability Index (ODI) higher than 20/100 and provided ODI questionnaires, return-to-work status at 3-, 6-, 12-, and 24-month follow-ups were analyzed. A total of 1769 patients were stratified according to the work subscale of the Fear-Avoidance Beliefs Questionnaire (FABQ-W) in high fear (FABQ-W ≥ 34/42) or low fear (FABQ-W < 34/42). Multivariate regression was used to search for preoperative factors, which might interact with FABQ-W. The higher-fear group showed a different recovery pattern, with higher levels of disability according to the ODI (total score, absolute change, frequency of clinically relevant change, and disability categories) and lower return-to-work ratios over the 24-month follow-up. High fear, high disability, greater age, female gender, smoking, and worse physical status at baseline were associated with worse ODI outcomes 2 years after the surgery. In summary, fear-avoidance beliefs significantly influence the speed and the entity of surgical outcomes in the working population. However, the contribution of FABQ-W in predicting long-term disability levels was limited., (Copyright © 2023 International Association for the Study of Pain.)

Discrimination between hematopoietic stem cells and leukemic stem cells remains a major challenge for acute myeloid leukemia immunotherapy. CAR T cells specific for the CD117 antigen can deplete malignant and healthy hematopoietic stem cells before consolidation with allogeneic hematopoietic stem cell transplantation in absence of cytotoxic conditioning. Here we exploit non-viral technology to achieve early termination of CAR T cell activity to prevent incoming graft rejection. Transient expression of an anti-CD117 CAR by mRNA conferred T cells the ability to eliminate CD117+ targets in vitro and in vivo . As an alternative approach, we used a Sleeping Beauty transposon vector for the generation of CAR T cells incorporating an inducible Caspase 9 safety switch. Stable CAR expression was associated with high proportion of T memory stem cells, low levels of exhaustion markers, and potent cellular cytotoxicity. Anti-CD117 CAR T cells mediated depletion of leukemic cells and healthy hematopoietic stem cells in NSG mice reconstituted with human leukemia or CD34+ cord blood cells, respectively, and could be terminated in vivo . The use of a non-viral technology to control CAR T cell pharmacokinetic properties is attractive for a first-in-human study in patients with acute myeloid leukemia prior to hematopoietic stem cell transplantation., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Nanofat is a relatively novel technique in fat grafting that has gained significant interest in the fields of regenerative medicine, aesthetic and translational research. It involves the extraction of autologous fat from a patient, which is then transformed into "nanofat", consisting of small fat particles with a diameter of less than 0.1 mm and containing high concentrations of stem cells and growth factors. This article focuses on the use of nanofat in facial rejuvenation and its potential for lipomodelling. Fat tissue is a "stem cell depot" and nanofat contains many stem cells that can differentiate into various cell types. The Lipogem technology, developed in 2013, enables the isolation of nanofat with an intact perivascular structure, utilizing the high concentration of mesenchymal stromal cells near the pericytes of the adipose vascular system. Nowadays nanofat is used primarily for cosmetic purposes particularly in rejuvenating and improving the appearance of the skin, especially the face. Indeed, it has wide applicability; it can be used to treat fine lines, wrinkles, acne scars, sun-damaged skin, scar repair, and as an alopecia treatment. However, further studies are needed to assess the long-term efficacy and safety of this technique. In conclusion, nanofat is a safe and minimally invasive option for tissue regeneration with considerable therapeutic potential. This study reviews the application and effects of nanofat in regenerative medicine and facial cosmetic surgery.

Aim: To compare three different posterior mono-segmental instrumented models with a Lateral Lumbar Interbody Fusion (LLIF) cage in L4-L5 based on finite element (FE) analysis., Material and Methods: Three different configurations of posterior instrumentation were created: 1. Bilateral posterior screws with 2 rods: Bilateral (B); 2. Left posterior rod and left pedicle screws in L4-L5: Unilateral (U); 3. Oblique posterior rod, left pedicle screw in L4, and right pedicle screw in L5: Oblique (O). The models were compared regarding the range of motion (ROM), stresses in the L4 and L5 pedicle screws, and posterior rods., Results: The Oblique and Unilateral models showed a lower decrease in ROM than the Bilateral model (O vs U vs B; 92% vs 95% vs 96%). In the L4 screw, a higher stress level was identified in the O than in the B model. Still, lower if compared to U. In the L5 screw, the highest stress values were observed with the O model in extension and flexion and the U model in lateral bending and axial rotation. The highest stress values for the rods were observed for the O model in extension, flexion, and axial rotation and the U model in lateral bending., Conclusion: The FE analysis showed that the three configurations significantly reduced the ROM. The stress analysis identified a substantially higher value for the rod and pedicle screws in oblique or unilateral configuration systems compared to the standard bilateral one. In particular, the oblique configuration has stress properties similar to the unilateral in lateral bending and axial rotation but is significantly higher in flexion-extension.

Aims: Wall shear stress (WSS) is involved in coronary artery plaque pathological mechanisms and modulation of gene expression. This study aims to provide a comprehensive haemodynamic and biological description of unstable (intact-fibrous-cap, IFC, and ruptured-fibrous-cap, RFC) and stable (chronic coronary syndrome, CCS) plaques and investigate any correlation between WSS and molecular pathways., Methods and Results: We enrolled 24 CCS and 25 Non-ST Elevation Myocardial Infarction-ACS patients with IFC (n = 11) and RFC (n = 14) culprit lesions according to optical coherence tomography analysis. A real-time PCR primer array was performed on peripheral blood mononuclear cells for 17 different molecules whose expression is linked to WSS. Computational fluid dynamics simulations were performed in high-fidelity 3D-coronary artery anatomical models for three patients per group. A total of nine genes were significantly overexpressed in the unstable patients as compared to CCS patients, with no differences between IFC and RFC groups (GPX1, MMP1, MMP9, NOS3, PLA2G7, PI16, SOD1, TIMP1, and TFRC) while four displayed different levels between IFC and RFC groups (TNFα, ADAMTS13, EDN1, and LGALS8). A significantly higher WSS was observed in the RFC group (p < 0.001) compared to the two other groups. A significant correlation was observed between TNFα (p < 0.001), EDN1 (p = 0.036), and MMP9 (p = 0.005) and WSS values in the RFC group., Conclusions: Our data demonstrate that IFC and RFC plaques are subject to different WSS conditions and gene expressions, suggesting that WSS profiling may play an essential role in the plaque instability characterization with relevant diagnostic and therapeutic implications in the era of precision medicine., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The pancreatic ductal adenocarcinoma (PDAC) microenvironment is highly fibrotic and hypoxic, with poor immune cell infiltration. Recently, we showed that nucleolin (NCL) inhibition normalizes tumour vessels and impairs PDAC growth. Methods: Immunocompetent mouse models of PDAC were treated by the pseudopeptide N6L, which selectively inhibits NCL. Tumour-infiltrating immune cells and changes in the tumour microenvironment were analysed. Results: N6L reduced the proportion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and increased tumour-infiltrated T lymphocytes (TILs) with an activated phenotype. Low-dose anti-VEGFR2 treatment normalized PDAC vessels but did not modulate the immune suppressive microenvironment. RNAseq analysis of N6L-treated PDAC tumours revealed a reduction of cancer-associated fibroblast (CAF) expansion in vivo and in vitro. Notably, N6L treatment decreased IL-6 levels both in tumour tissues and in serum. Treating mPDAC by an antibody blocking IL-6 reduced the proportion of Tregs and MDSCs and increased the amount of TILs, thus mimicking the effects of N6L. Conclusions: These results demonstrate that NCL inhibition blocks the amplification of lymphoid and myeloid immunosuppressive cells and promotes T cell activation in PDAC through a new mechanism of action dependent on the direct inhibition of the tumoral stroma.