Targeting Pathogenic Myelopoiesis in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly inflammatory and immunosuppressive tumor microenvironment. During cancer progression, tumor-derived inflammatory signals can alter hematopoiesis and promote the expansion of myeloid cells with pro-tumorigenic functions. Inflammatory cytokines, including interleukin-1 beta (IL-1β), may act on hematopoietic stem and progenitor cells (HSPCs), inducing genomic and metabolic reprogramming and favoring myeloid-biased hematopoiesis. Previous and preliminary findings suggest that IL-1β may contribute to pathogenic inflammation in PDAC and to systemic conditioning of the immune system. The study hypothesis is that IL-1β-associated tumor inflammation reprograms hematopoietic progenitor compartments, leading to persistent generation of pro-inflammatory myeloid cells that may contribute to PDAC progression and recurrence. This is a monocentric, prospective observational cohort study designed to characterize pathogenic myelopoiesis in patients with PDAC. The study will include 50 patients with newly diagnosed, non-metastatic, treatment-naïve PDAC and 50 age-matched control patients. Control patients will be recruited among individuals with intraductal papillary mucinous neoplasm (IPMN) under surveillance at the Pancreatic Cystic Lesion outpatient clinic, with no evidence of pancreatic malignancy at enrollment. Controls will be selected to match the age of PDAC patients within a range of ±5 years whenever feasible. The primary objective is to identify the molecular drivers of pathogenic myelopoiesis in PDAC patients. At baseline, quantitative and qualitative differences between PDAC patients and age-matched controls will be evaluated in the frequency and phenotype of circulating myeloid and progenitor cell populations using high-dimensional flow cytometry. Transcriptional profiles of circulating myeloid cells and HSPCs will also be characterized, including differentially expressed genes, gene ontology annotations, and gene regulatory networks. After informed consent and verification of eligibility criteria, demographic and relevant clinical data will be collected. All participants will undergo a single peripheral blood collection of approximately 14 mL specifically for research purposes. In PDAC patients, blood will be collected at baseline before initiation of any anti-tumor treatment. Control patients will undergo the same baseline blood sampling for comparator translational analyses. Peripheral blood sampling is the only study-specific procedure; no investigational medicinal products or therapeutic interventions will be administered as part of the study. Blood samples will undergo translational laboratory analyses aimed at characterizing circulating myeloid cells, progenitor cells, and HSPC-related transcriptional programs. Planned analyses include high-dimensional flow cytometry and transcriptomic and epigenetic analyses. Biological samples will be processed according to established laboratory procedures and used exclusively for the analyses described in the study protocol. In addition to the human translational component, the research project includes experimental studies aimed at investigating the persistence and molecular determinants of IL-1β-induced reprogramming of bone marrow progenitor cells. In mouse models, the persistence of IL-1β-dependent reprogramming will be evaluated through characterization of circulating and bone marrow myeloid populations, transcriptional profiles, and tumor growth following experimental tumor challenge. Exploratory analyses will investigate transcriptional and epigenetic programs associated with IL-1β-induced inflammatory memory, including differential gene expression, chromatin accessibility, histone modifications, and transcription factor regulatory programs. Candidate mechanisms identified experimentally will be evaluated in relation to IL-1β-dependent signatures detected in circulating monocytes from PDAC patients compared with age-matched controls. PDAC patients will be followed clinically for 12 months after enrollment. No additional protocol-mandated visits or procedures are required during follow-up. Clinical information will be obtained exclusively from routine standard-of-care visits and medical records and will include, where available, treatments received, disease status, recurrence, progression, and survival. These data will be used to explore associations between baseline pathogenic myelopoiesis-related profiles and subsequent clinical outcomes. Control patients will not undergo study-specific follow-up after baseline assessment. Statistical analyses will primarily be descriptive and exploratory. Baseline biological features will be compared between PDAC patients and age-matched controls using appropriate parametric or non-parametric statistical methods and bioinformatic approaches for high-dimensional datasets. Associations between baseline biological features and clinical outcomes will also be explored within the PDAC cohort. The planned enrollment period is 2 years. PDAC patients will participate in clinical follow-up for 12 months, while control patients will undergo baseline assessment only. The overall study duration is expected to be 3 years.