The Tumour, the Host and Chemotherapy Response in Pancreatic Cancer

Pancreatic cancer is one of the most aggressive malignancies, with a 5-year overall survival of approximately 10%.Late detection, limited treatment options, dense desmoplastic stroma, immunosuppression, low mutational burden, and inherent chemoresistance all contribute to the poor prognosis.This thesis aimed to investigate tumour and host related factors influencing chemotherapy response in pancreatic cancer from genetic, proteomic, and immunological perspectives.The work was conducted within the prospective CHAMP study, including patients across all disease stages.Longitudinal blood samples and resected tumour tissue were analysed using circulating tumour DNA (ctDNA) sequencing, multiplex immunofluorescence, proximity extension assay, and flow cytometry.Paper I explored the temporal tumour heterogeneity by sequencing ctDNA from 60 patients during chemotherapy using a customised gene panel.Positive versus negative ctDNA was not prognostic, but in palliative patients, an independent and durable prognostic cut-off could be calculated from the absolute number of mutated DNA molecules.Genetic alterations detected in ctDNA largely mirrored those in tumour tissue, and actionable mutations were identified in five patients, supporting ctDNA profiling as a clinically relevant tool for both prognostication and precision oncology.Paper II characterised systemic levels of the proteoglycan decorin in 124 patients (30 adjuvant, 94 palliative) and local expression in tumour samples from 27 resected cases.Systemic decorin increased after chemotherapy in palliative patients, and the rate of change was an independent prognostic marker in both adjuvant and palliative patients.High stromal decorin within tumours predicted longer survival, while decorin positive B cells were linked to shorter survival, highlighting context dependent roles of decorin in pancreatic cancer biology.Paper III examined chemotherapy induced changes in the peripheral immune landscape in 93 palliative patients.FOLFIRINOX was the strongest immune modulator, causing pronounced reductions in several chemoattractant cytokines.Nine serum proteins showed significant associations with overall survival.Circulating B cells also emerged as an independent negative prognostic factor, with high B cell frequencies linked to an expanded naïve B cell compartment and elevated IL-10 expression, suggesting a more immunosuppressed systemic environment.Together, these studies provide complementary insights into how tumour derived and host mediated factors shape chemotherapy responses in pancreatic cancer, offering potential avenues for improved biomarker guided patient stratification and treatment optimisation.