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Cortisol is a glucocorticoid hormone that has immunosuppressive function. Elevated basal cortisol levels are present in patients with some kinds of cancers, but its role in the microenvironment of pancreatic adenocarcinoma (PAAD) remains unclear. This study analyzed the expression of genes involved in cortisol generation by using high-throughput sequencing data from TCGA portal and found HSD11B1 was significantly upregulated in patients with PAAD. The correlations between HSD11B1 level and the expression of 23 immunosuppressive receptors were analyzed by Spearman's correlation analysis. The function of HSD11B1 was examined in primary NK cells and PAAD cell lines. The levels of cortisol in medium and cell lysates were detected by ELISA. In vitro killing assay was used to evaluate the cytotoxicity of NK cells. Cell surface levels of CD96, Tim-3, PD-1, TIGIT, CTLA-4, NKp46, NKp30, NKD2G and LFA-1A, and intracellular levels of CD107a and IFN-γ were examined by flow cytometry. We observed that patients with higher HSD11B1 level had shorter survival time. HSD11B1 is positively correlated with the mRNA levels of 11 immunosuppressive receptors in PAAD. Higher HSD11B1 level relates to reduced abundance of activated NK cells in the tumors. HSD11B1 overexpressed NK cells exhibit exhausted phenotype with increased cortisol production, reduced viability, and reduced cytotoxicity against cancer cells. Overexpression of HSD11B1 did not change the viability of tumor cells but upregulated cortisol production. Targeting HSD11B1 by a specific inhibitor improved the NK cells responsiveness. In conclusion, HSD11B1 is upregulated in patients with PAAD, and higher HSD11B1 level is related to poor prognosis. Upregulation of HSD11B1 in NK and tumor cells increased the production and secretion of cortisol and induces NK cell exhaustion.

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A blood test that enables surveillance for early-stage pancreatic ductal adenocarcinoma (PDAC) is an urgent need. Independent laboratories have reported PDAC biomarkers that could improve biomarker performance over CA19-9 alone, but the performance of the previously reported biomarkers in combination is not known. Therefore, we conducted a coordinated case/control study across multiple laboratories using common sets of blinded training and validation samples (132 and 295 plasma samples, respectively) from PDAC patients and non-PDAC control subjects representing conditions under which surveillance occurs. We analyzed the training set to identify candidate biomarker combination panels using biomarkers across laboratories, and we applied the fixed panels to the validation set. The panels identified in the training set, CA19-9 with CA199.STRA, LRG1, TIMP-1, TGM2, THSP2, ANG, and MUC16.STRA, achieved consistent performance in the validation set. The panel of CA19-9 with the glycan biomarker CA199.STRA improved sensitivity from 0.44 with 0.98 specificity for CA19-9 alone to 0.71 with 0.98 specificity (p < 0.001, 1000-fold bootstrap). Similarly, CA19-9 combined with the protein biomarker LRG1 and CA199.STRA improved specificity from 0.16 with 0.94 sensitivity for CA19-9 to 0.65 with 0.89 sensitivity (p < 0.001, 1000-fold bootstrap). We further validated significantly improved performance using biomarker panels that did not include CA19-9. This study establishes the effectiveness of a coordinated study of previously discovered biomarkers and identified panels of those biomarkers that significantly increased the sensitivity and specificity of early-stage PDAC detection in a rigorous validation trial.

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Background: Lactate dehydrogenase A (LDHA) plays a crucial role in the final step of anaerobic glycolysis, converting L-lactate and NAD+ to pyruvate and nicotinamide adenine dinucleotide (NADH). Its high expression has been linked to tumorigenesis and patient survival in various human cancers. However, the full implications of LDHA's role and its correlation with clinicopathological features in pancreatic adenocarcinoma (PAAD) remain to be fully understood. This study was thus conducted to elucidate the specific functions of LDHA in PAAD, with the aim of providing more robust evidence for clinical diagnosis and treatment. Methods: In an extensive systems analysis, we searched through numerous databases, including The Cancer Genome Atlas (TCGA) and Oncomine. Our objective was to clarify the clinical implications and functional role of LDHA in PAAD. Bioinformatics was used to identify the biological function of LDHA expression and its correlation with tumor immune status. Results: Our analysis revealed that the LDHA gene is overexpressed in PAAD and that this upregulation was associated with a worse patient prognosis. Through gene set enrichment analysis, we found that LDHA's influence on PAAD is linked to signaling pathways involving Kirsten rat sarcoma viral oncogene homolog (K-Ras), transforming growth factor-ß (TGF-ß), and hypoxia inducible factor-1 (HIF-1). Mutation of K-Ras could upregulate its own expression and was positively correlated with LDHA expression. Moreover, our data demonstrated that LDHA expression was linked to immune infiltration and poor prognosis in PAAD, indicating its role in disease pathogenesis. Overexpression of LDHA may suppress tumor immunity, suggesting it as a potential target for the diagnosis and treatment of PAAD, thus providing new insights into managing this aggressive cancer. Conclusions: Overall, our results showed that LDHA as a prognostic biomarker could serve as a novel target for future PAAD immunotherapy.

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Background: Pancreatic adenocarcinoma (PAAD) is a highly lethal malignancy characterized by aggressive growth and poor prognosis. Understanding the molecular mechanisms underlying PAAD is crucial for developing effective therapies. This study aimed to explore the role of TM4SF1 and other key genes in PAAD progression, their prognostic implications, and therapeutic opportunities. Methods: Differential gene expression analysis was performed using PAAD and normal tissue samples to identify upregulated genes, with TM4SF1 emerging as significantly elevated in PAAD. Functional enrichment analysis elucidated associated signaling pathways. A prognostic model comprising BPIFB4, PLEKHN1, CPTP, DVL1, and DDR1 was developed using least absolute shrinkage and selection operator (LASSO) regression and validated in an independent cohort. Genetic mutation analysis provided insights into the functional significance of identified genes. Pharmacogenomic analysis examined associations between gene expression and drug sensitivity. Experimental validation included quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analyses to confirm gene expression patterns and protein levels. Results: Lower TM4SF1 expression correlated with enhanced anti-tumor immune activity in PAAD, suggesting a complex interplay between genetic expression and immune response. The prognostic model showed robust associations with patient survival outcomes, validated across diverse patient cohorts. Genetic mutation analysis highlighted potential therapeutic targets. Pharmacogenomic analysis revealed correlations between gene expression profiles and drug responsiveness, suggesting personalized treatment strategies. Experimental validation confirmed elevated TM4SF1 levels in tumor tissues and demonstrated its role in promoting cancer cell proliferation and colony formation. Conclusions: This study advances understanding of the molecular landscape of PAAD, emphasizing TM4SF1 as a key regulator and potential therapeutic target. The integration of genetic expression, immune response dynamics, and pharmacogenomics offers a multifaceted approach to personalized treatment strategies for PAAD, paving the way for improved patient outcomes and novel therapeutic interventions. Further research is warranted to elucidate the clinical utility of targeting TM4SF1 and other identified genes in PAAD management.

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INTRODUCTION: Pancreatic adenocarcinoma (PDAC) is becoming a public health issue with a 5-years survival rate around 10%. Patients with PDAC are often sarcopenic, which impacts postoperative outcome. At the same time, overweight population is increasing and adipose tissue promotes tumor related-inflammation. With several studies supporting independently these data, we aimed to assess if they held an impact on survival when combined. METHODS: We included 232 patients from two university hospitals (CHU de Lille, Institut Paoli Calmette), from January 2011 to December 2018, who underwent Pancreaticoduodenectomy (PD) for resectable PDAC. Preoperative CT scan was used to measure sarcopenia and visceral fat according to international cut-offs. Neutrophil to lymphocyte (NLR) and platelet to lymphocyte ratios (PLR) were used to measure inflammation. For univariate and multivariate analyses, the Cox proportional-hazard model was used. P-values below 0.05 were considered significant. RESULTS: Sarcopenic patients with visceral obesity were less likely to survive than the others in multivariate analysis (OS, HR 1.65, p= 0.043). Cutaneous obesity did not influence survival. We also observed an influence on survival when we studied sarcopenia with visceral obesity (OS, p= 0.056; PFS, p = 0.014), sarcopenia with cutaneous obesity (PFS, p= 0.005) and sarcopenia with PLR (PFS, p= 0.043). This poor prognosis was also found in sarcopenic obese patients with high PLR (OS, p= 0.05; PFS, p= 0.01). CONCLUSION: Sarcopenic obesity was associated with poor prognosis after PD for PDAC, especially in patients with systemic inflammation. Pre operative management of these factors should be addressed in pancreatic cancer patients.

Asunto(s)

Adenocarcinoma , Pancreatectomía , Neoplasias Pancreáticas , Sarcopenia , Humanos , Sarcopenia/complicaciones , Sarcopenia/mortalidad , Sarcopenia/patología , Sarcopenia/etiología , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/complicaciones , Masculino , Femenino , Anciano , Tasa de Supervivencia , Pancreatectomía/mortalidad , Pancreatectomía/efectos adversos , Pronóstico , Persona de Mediana Edad , Adenocarcinoma/cirugía , Adenocarcinoma/patología , Adenocarcinoma/mortalidad , Adenocarcinoma/complicaciones , Estudios de Seguimiento , Estudios Retrospectivos , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Síndrome de Respuesta Inflamatoria Sistémica/mortalidad , Pancreaticoduodenectomía/efectos adversos , Pancreaticoduodenectomía/mortalidad , Carcinoma Ductal Pancreático/cirugía , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/complicaciones

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Insulin-like growth factor binding protein 2 (IGFBP2) is overexpressed in tumor tissues of several malignancies, including pancreatic cancer. Because of its role in tumor progression, IGFBP2 has been investigated as a tumor biomarker. However, little is known about its utility in pancreatic cancer. Plasma IGFBP2 levels were determined using enzyme-linked immunosorbent assay in 75 patients with pancreatic ductal adenocarcinoma (PDAC), 73 matched healthy controls, and 17 chronic pancreatitis patients. Our results showed that the plasma IGFPB2 level was significantly higher in PDAC patients than in patients with chronic pancreatitis and healthy controls. At a cut-off value of 333.9 ng/mL, the specificity and sensitivity were 78.08 and 65.33%, respectively. IGFBP2 level alone did not outperform carbohydrate antigen 19-9 (CA19-9) in diagnostic accuracy, but it successfully identified 9 out of 24 PDAC patients who were misidentified by CA19-9. The combination of IGFBP2 and CA19-9 was more accurate in the detection of PDAC than CA19-9 alone. IGFBP2 was more accurate than the other in discriminating between chronic pancreatitis and PDAC. Plasma IGFBP2, rather than CA19-9, was higher in the new-onset diabetes, lymph node involvement, and distant metastasis subgroups. IGFBP2 level was notably higher in stage IV cases than in stage I/II or stage III disease. However, CA19-9 did not show a difference between stages. After adjusting for lymph node involvement and distant metastasis, plasma IGFBP2 was identified as an independent prognostic marker for PDAC. The median survival time for patients with an IGFBP2 level ≥333.9 ng/mL was significantly shorter than that for patients with an IGFBP2 level <333.9 ng/mL. Marked elevation of plasma IGFBP2 in PDAC is associated with poorer survival. IGFBP2 may be considered as a supplementary biomarker for the diagnosis and prognostic prediction in Chinese pancreatic cancer patients.

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A 10-y-old spayed female Cavalier King Charles Spaniel dog was presented to the Veterinary Teaching Hospital because of recurrent chronic abscesses on the distal pelvic limbs, fever, lethargy, lameness of unknown etiology, and chronic pancreatitis. Sterile nodular panniculitis was diagnosed after an extensive workup, and the dog initially responded to immunosuppressive therapy, but relapse and spread of cutaneous lesions and acute lameness occurred after 11 mo, and euthanasia was elected. Postmortem examination confirmed hyalinizing pancreatic adenocarcinoma with pancreatitis, panniculitis, polyarthritis (PPP), and osteomyelitis. Histopathology and bacterial and fungal cultures were supportive of a sterile process, specifically the PPP syndrome, which is a rare, potentially life-threatening, systemic manifestation of pancreatic disease in both people and animals. To our knowledge, a clinicopathologic description of a hyalinizing pancreatic adenocarcinoma associated with this rare syndrome has not been reported previously in a dog.

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Pancreatic adenocarcinoma is an aggressive malignancy that often presents with advanced disease. Accurate staging is essential for treatment planning and shared decision-making with patients. Staging laparoscopy is a minimally invasive procedure that can detect radiographically occult metastatic disease. Its routine use with the collection of peritoneal washings in patients with pancreatic cancer remains controversial. We, herein, review the current literature concerning staging laparoscopy and peritoneal washings in patients with pancreatic cancer.

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Adenocarcinoma , Laparoscopía , Estadificación de Neoplasias , Neoplasias Pancreáticas , Lavado Peritoneal , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Laparoscopía/métodos , Lavado Peritoneal/métodos , Adenocarcinoma/diagnóstico , Adenocarcinoma/patología , Adenocarcinoma/cirugía

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While pancreatic adenocarcinoma requires surgical resection definitive cure, treatment paradigms are shifting toward a neoadjuvant approach to systemic therapy. Rationale is twofold: micro-metastatic disease is likely present in a majority of patients, reinforcing the importance of systemic therapy regardless of resectability; moreover, systemic therapy is well-tolerated and improves surgical outcomes when delivered preoperatively. Second, a neoadjuvant approach allows for selection of biology and patients most likely to benefit from potentially morbid surgery. This review examines the increasing body of evidence in support of empiric neoadjuvant therapy in pancreatic adenocarcinoma.

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Adenocarcinoma , Terapia Neoadyuvante , Pancreatectomía , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/cirugía , Terapia Neoadyuvante/métodos , Adenocarcinoma/terapia , Adenocarcinoma/cirugía , Adenocarcinoma/patología , Pancreatectomía/métodos , Quimioterapia Adyuvante/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico

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BACKGROUND: With poor prognosis and high mortality, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Standard of care therapies for PDAC have included gemcitabine for the past three decades, although resistance often develops within weeks of chemotherapy initiation through an array of possible mechanisms. METHODS: We reanalyzed publicly available RNA-seq gene expression profiles of 28 PDAC patient-derived xenograft (PDX) models before and after a 21-day gemcitabine treatment using our validated analysis pipeline to identify molecular markers of intrinsic and acquired resistance. RESULTS: Using normalized RNA-seq quantification measurements, we first identified oxidative phosphorylation and interferon alpha pathways as the two most enriched cancer hallmark gene sets in the baseline gene expression profile associated with intrinsic gemcitabine resistance and sensitivity, respectively. Furthermore, we discovered strong correlations between drug-induced expression changes in glycolysis and oxidative phosphorylation genes and response to gemcitabine, which suggests that these pathways may be associated with acquired gemcitabine resistance mechanisms. Thus, we developed prediction models using baseline gene expression profiles in those pathways and validated them in another dataset of 12 PDAC models from Novartis. We also developed prediction models based on drug-induced expression changes in genes from the Molecular Signatures Database (MSigDB)'s curated 50 cancer hallmark gene sets. Finally, pathogenic TP53 mutations correlated with treatment resistance. CONCLUSION: Our results demonstrate that concurrent upregulation of both glycolysis and oxidative phosphorylation pathways occurs in vivo in PDAC PDXs following gemcitabine treatment and that pathogenic TP53 status had association with gemcitabine resistance in these models. Our findings may elucidate the molecular basis for gemcitabine resistance and provide insights for effective drug combination in PDAC chemotherapy.

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Desoxicitidina , Resistencia a Antineoplásicos , Gemcitabina , Neoplasias Pancreáticas , Proteína p53 Supresora de Tumor , Ensayos Antitumor por Modelo de Xenoinjerto , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Resistencia a Antineoplásicos/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Animales , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Ratones , Reprogramación Metabólica

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Purpose: 68Ga-labeled fibroblast activation protein inhibitor (FAPI) is a novel PET tracer with great potential for staging pancreatic cancer. Data on locally advanced or recurrent disease is sparse, especially on tracer uptake before and after high dose chemoradiotherapy (CRT). The aim of this study was to evaluate [68Ga]Ga-FAPI-46 PET/CT staging in this setting. Methods: Twenty-seven patients with locally recurrent or locally advanced pancreatic adenocarcinoma (LRPAC n = 15, LAPAC n = 12) in stable disease or partial remission after chemotherapy underwent FAPI PET/CT and received consolidation CRT in stage M0 with follow-up FAPI PET/CT every three months until systemic progression. Quantitative PET parameters SUVmax, SUVmean, FAPI-derived tumor volume and total lesion FAPI-uptake were measured in baseline and follow-up PET/CT scans. Contrast-enhanced CT (ceCT) and PET/CT data were evaluated blinded and staged according to TNM classification. Results: FAPI PET/CT modified staging compared to ceCT alone in 23 of 27 patients in baseline, resulting in major treatment alterations in 52% of all patients (30%: target volume adjustment due to N downstaging, 15%: switch to palliative systemic chemotherapy only due to diffuse metastases, 7%: abortion of radiotherapy due to other reasons). Regarding follow-up scans, major treatment alterations after performing FAPI PET/CT were noted in eleven of 24 follow-up scans (46%) with switch to systemic chemotherapy or best supportive care due to M upstaging and ablative radiotherapy of distant lymph node and oligometastasis. Unexpectedly, in more than 90 % of the follow-up scans, radiotherapy did not induce local fibrosis related FAPI uptake. During the first follow-up, all quantitative PET metrics decreased, and irradiated lesions showed significantly lower FAPI uptake in locally controlled disease (SUVmax p = 0.047, SUVmean p = 0.0092) compared to local failure. Conclusion: Compared to ceCT, FAPI PET/CT led to major therapeutic alterations in patients with LRPAC and LAPAC prior to and after radiotherapy, which might help identify patients benefiting from adjustments in every treatment stage. FAPI PET/CT should be considered a useful diagnostic tool in LRPAC or LAPAC before and after CRT.

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Quimioradioterapia , Radioisótopos de Galio , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Neoplasias Pancreáticas , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Quimioradioterapia/métodos , Adulto , Radiofármacos , Adenocarcinoma/terapia , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/patología , Adenocarcinoma/tratamiento farmacológico , Anciano de 80 o más Años , Quinolinas

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BACKGROUND: Knowledge about environmental pancreatic adenocarcinoma (PA) risk factors, including pesticide exposure, remains limited. Organochlorine (OC) accumulates in adipose tissue and can help reflect long-term exposure. PATIENTS AND METHODS: Age and body mass index (BMI) of patients with PA were matched with those undergoing a surgery for a benign disease on age and BMI (1:1). Targeted analyses screened 345 pesticides and metabolites, including 29 OC, in adipose tissue and urine samples. The primary aim was to investigate the association between organochlorine concentrations in visceral fat or urine, and PA. Adjusted conditional logistic regressions were carried out accounting for multiple testing. RESULTS: Trans-nonachlor (odds ratio [OR] = 1.325, 95% confidence interval [CI] [1.108-1.586]), cis-nonachlor (OR = 15.433, 95% CI [2.733-87.136]), Mirex (OR = 2.853, 95% CI [1.213-6.713]) and 4,4 DDE (OR = 1.019, 95% CI [1.005-1.034]) in fat and a greater number of positive samples (OR = 1.758 95% CI [1.11-2.997]) were significantly associated with higher odds of PA. In contrast, as awaited, urine samples did not yield any statistically significant associations for all tested pesticides. CONCLUSION: Some OCs were associated with higher odds of PA. The underlying mechanisms of pancreatic aggression need to be investigated to refine these findings. TRIAL REGISTRATION: Clinicaltrials.gov NCT04429490.

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Despite many studies focusing on the prognostic biomarkers in pancreatic adenocarcinomas (PAADs), there is ill-informed about the relationships between their genomic features and immune characteristics. Herein, we deeply investigated the involvement of major driver mutation subtypes with immunophenotypes impacting PAAD outcomes. Based on public data analyses of RNA expression-based immune subtypes in PAAD, in contrast to KRAS G12D & TP53 co-mutant patients with poor outcomes, the best immune subtype C3 (inflammatory) characterized by high Th1/Th2 ratio was relatively enriched in KRASnon-G12DTP53wt patients with better survival, whereas the inferior subtype C2 (IFN-γ dominant) with low Th1/Th2 ratio was more common in the former than in the latter. Moreover, contrary to the highly immunosuppressive microenvironment (high Treg, high ratio of Treg to tumor-specific CD4+ T cell) in KRASG12DTP53mut patients, KRASG12VTP53wt individuals exhibited an inflamed context profiled by multiplex immunohistochemistry. It could be responsible for their outstanding survival advantage over others in postsurgical PAAD patients receiving adjuvant chemotherapy as shown by our cohort. Together, KRASG12VTP53wt may be a promising biomarker for prognostic evaluation and screening certain candidates with PAAD to get desirable survival benefit from adjuvant chemotherapy.

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Biomarcadores de Tumor , Inmunofenotipificación , Mutación , Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas p21(ras) , Microambiente Tumoral , Proteína p53 Supresora de Tumor , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Proteínas Proto-Oncogénicas p21(ras)/genética , Microambiente Tumoral/inmunología , Proteína p53 Supresora de Tumor/genética , Pronóstico , Biomarcadores de Tumor/genética , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Adenocarcinoma/mortalidad , Masculino , Femenino

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AIM: The main focus of this study is to explore the molecular mechanism of IRF7 regulation on RPS18 transcription in M1-type macrophages in pancreatic adenocarcinoma (PAAD) tissue, as well as the transfer of RPS18 by IRF7 via exosomes to PAAD cells and the regulation of ILF3 expression. METHODS: By utilising single-cell RNA sequencing (scRNA-seq) data and spatial transcriptomics (ST) data from the Gene Expression Omnibus database, we identified distinct cell types with significant expression differences in PAAD tissue. Among these cell types, we identified those closely associated with lipid metabolism. The differentially expressed genes within these cell types were analysed, and target genes relevant to prognosis were identified. Flow cytometry was employed to assess the expression levels of target genes in M1 and M2 macrophages. Cell lines with target gene knockout were constructed using CRISPR/Cas9 editing technology, and cell lines with target gene knockdown and overexpression were established using lentiviral vectors. Additionally, a co-culture model of exosomes derived from M1 macrophages with PAAD cells was developed. The impact of M1 macrophage-derived exosomes on the lipid metabolism of PAAD cells in the model was evaluated through metabolomics analysis. The effects of M1 macrophage-derived exosomes on the viability, proliferation, division, migration and apoptosis of PAAD cells were assessed using MTT assay, flow cytometry, EdU assay, wound healing assay, Transwell assay and TUNEL staining. Furthermore, a mouse PAAD orthotopic implantation model was established, and bioluminescence imaging was utilised to assess the influence of M1 macrophage-derived exosomes on the intratumoural formation capacity of PAAD cells, as well as measuring tumour weight and volume. The expression of proliferation-associated proteins in tumour tissues was examined using immunohistochemistry. RESULTS: Through combined analysis of scRNA-seq and ST technologies, we discovered a close association between M1 macrophages in PAAD samples and lipid metabolism signals, as well as a negative correlation between M1 macrophages and cancer cells. The construction of a prognostic risk score model identified RPS18 and IRF7 as two prognostically relevant genes in M1 macrophages, exhibiting negative and positive correlations, respectively. Mechanistically, it was found that IRF7 in M1 macrophages can inhibit the transcription of RPS18, reducing the transfer of RPS18 to PAAD cells via exosomes, consequently affecting the expression of ILF3 in PAAD cells. IRF7/RPS18 in M1 macrophages can also suppress lipid metabolism, cell viability, proliferation, migration, invasion and intratumoural formation capacity of PAAD cells, while promoting cell apoptosis. CONCLUSION: Overexpression of IRF7 in M1 macrophages may inhibit RPS18 transcription, reduce the transfer of RPS18 from M1 macrophage-derived exosomes to PAAD cells, thereby suppressing ILF3 expression in PAAD cells, inhibiting the lipid metabolism pathway, and curtailing the viability, proliferation, migration, invasion of PAAD cells, as well as enhancing cell apoptosis, ultimately inhibiting tumour formation in PAAD cells in vivo. Targeting IRF7/RPS18 in M1 macrophages could represent a promising immunotherapeutic approach for PAAD in the future.

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Factor 7 Regulador del Interferón , Metabolismo de los Lípidos , Macrófagos , Neoplasias Pancreáticas , Análisis de la Célula Individual , Animales , Humanos , Ratones , Línea Celular Tumoral , Factor 7 Regulador del Interferón/genética , Factor 7 Regulador del Interferón/metabolismo , Metabolismo de los Lípidos/genética , Macrófagos/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Análisis de la Célula Individual/métodos

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Pancreatic adenocarcinoma (PDAC) is one the most intractable cancers, in part due to its highly inflammatory microenvironment and paucity of infiltrating dendritic cells (DCs). Here, we find that genetic ablation or antibody blockade of tumor necrosis factor receptor 1 (TNFR1) enhanced intratumor T cell activation and slowed PDAC growth. While anti-PD-1 checkpoint inhibition alone had little effect, it further enhanced intratumor T cell activation in combination with anti-TNFR1. The major cellular alteration in the tumor microenvironment in the absence of TNFR1 signaling was a large increase in DC number and immunostimulatory phenotype. This may reflect a direct effect on DCs, because TNF induced TNFR1-dependent apoptosis of bone-marrow-derived DCs. The therapeutic response to anti-TNFR1 alone was superior to the combination of DC-activating agonistic anti-CD40 and Flt3 ligand (Flt3L). These observations suggest that targeting TNFR1, perhaps in concert with other strategies that promote DC generation and mobilization, may have therapeutic benefits.

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BACKGROUND: Pancreatic adenocarcinomas (PAADs) often exhibit a "cold" or immunosuppressive tumor milieu, which is associated with resistance to immune checkpoint blockade therapy; however, the underlying mechanisms are incompletely understood. Here, we aimed to improve our understanding of the molecular mechanisms occurring in the tumor microenvironment and to identify biomarkers, therapeutic targets, and potential drugs to improve PAAD treatment. METHODS: Patients were categorized according to immunologically hot or cold PAAD subtypes with distinct disease outcomes. Cox regression and weighted correlation network analysis were performed to construct a novel gene signature, referred to as 'Downregulated in hot tumors, Prognostic, and Immune-Related Genes' (DPIRGs), which was used to develop prognostic models for PAAD via machine learning (ML). The role of DPIRGs in PAAD was comprehensively analyzed, and biomarker genes able to distinguish PAAD immune subtypes and predict prognosis were identified by ML. The expression of biomarkers was verified using public single-cell transcriptomic and proteomic resources. Drug candidates for turning cold tumors hot and corresponding target proteins were identified via molecular docking studies. RESULTS: Using the DPIRG signature as input data, a combination of survival random forest and partial least squares regression Cox was selected from 137 ML combinations to construct an optimized PAAD prognostic model. The effects and molecular mechanisms of DPIRGs were investigated by analysis of genetic/epigenetic alterations, immune infiltration, pathway enrichment, and miRNA regulation. Biomarkers and potential therapeutic targets, including PLEC, TRPV1, and ITGB4, among others, were identified, and the cell type-specific expression of the biomarkers was validated. Drug candidates, including thalidomide, SB-431542, and bleomycin A2, were identified based on their ability to modulate DPIRG expression favorably. CONCLUSIONS: By combining multiple ML algorithms, we developed a novel prognostic model with excellent performance in PAAD cohorts. ML also proved to be powerful for identifying biomarkers and potential targets for improved PAAD patient stratification and immunotherapy.

Asunto(s)

Adenocarcinoma , Biomarcadores de Tumor , Regulación Neoplásica de la Expresión Génica , Aprendizaje Automático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/inmunología , Biomarcadores de Tumor/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma/metabolismo , Pronóstico , Simulación del Acoplamiento Molecular , Microambiente Tumoral , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Masculino , Transcriptoma/genética , Femenino

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BACKGROUND AND OBJECTIVES: Patients with localized pancreatic adenocarcinoma who do not respond to neoadjuvant therapy present a challenge. We sought to define the characteristics and outcomes of those patients to guide clinical practice. METHODS: Patients included were those without evidence of biochemical or radiographic response and no evidence of distant progression at the first reassessment after initiation of therapy. RESULTS: Of the 45 patients in the cohort, 23 (51.1%) proceeded to surgical exploration with all but one of those undergoing resection. The median overall survival of the study cohort was 28.6 and 48.6 months in those who underwent resection. A total of 13 patients (28.9%) underwent chemotherapy switch (CS) during their course of neoadjuvant therapy. The CS cohort demonstrated higher rates of radiologic progression (25% vs. 10%, p = 0.329), new or worse vascular involvement (58.3% vs. 30%, p = 0.082), and CA 19-9 increase (30.8% vs. 12.9%, p = 0.209) at initial re-staging. Despite this, overall survival was similar between the two groups (20.7 vs. 28.7 months, p = 0.674). CONCLUSION: Non-responders to first-line neoadjuvant therapy have poor rates of curative-intent resection. However, resection should be undertaken when feasible. CS may be considered in patients who do not respond to first-line chemotherapy.

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Hepato-Pancreato-Biliary (HPB) malignancies constitute a highly aggressive group of cancers that have a dismal prognosis. Patients not amenable to curative intent surgical resection are managed with systemic chemotherapy which, however, confers little survival benefit. Antibody-Drug Conjugates (ADCs) are tripartite compounds that merge the intricate selectivity and specificity of monoclonal antibodies with the cytodestructive potency of attached supertoxic payloads. In view of the unmet need for drugs that will enhance the survival rates of HPB cancer patients, the assessment of ADCs for treating HPB malignancies has become the focus of extensive clinical and preclinical investigation, showing encouraging preliminary results. In the current review, we offer a comprehensive overview of the growing body of evidence on ADC approaches tested for HPB malignancies. Starting from a concise discussion of the functional principles of ADCs, we summarize here all available data from preclinical and clinical studies evaluating ADCs in HPB cancers.

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Neoplasias del Sistema Biliar , Inmunoconjugados , Neoplasias Hepáticas , Neoplasias Pancreáticas , Humanos , Inmunoconjugados/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Antineoplásicos Inmunológicos/uso terapéutico

RESUMEN

This study aimed to introduce specific image feature analysis, focusing on pancreatic margins, and to provide a quantitative measure of edge irregularity, evidencing correlations with the presence/absence of pancreatic adenocarcinoma. We selected 50 patients (36 men, 14 women; mean age 63.7 years) who underwent Multi-detector computed tomography (MDCT) for the staging of pancreatic adenocarcinoma of the tail of the pancreas. Computer-assisted quantitative edge analysis was performed on the border fragments in MDCT images of neoplastic and healthy glandular parenchyma, from which we obtained the root mean square deviation SD of the actual border from the average boundary line. The SD values relative to healthy and neoplastic borders were compared using a paired t-test. A significant SD difference was observed between healthy and neoplastic borders. A threshold SD value was also found, enabling the differentiation of adenocarcinoma with 96% specificity and sensitivity. We introduced a quantitative measure of boundary irregularity, which correlates with the presence/absence of pancreatic adenocarcinoma. Quantitative edge analysis can be promptly performed on select border fragments in MDCT images, providing a useful supporting tool for diagnostics and a possible starting point for machine learning recognition based on lower-dimensional feature space.