Functional and transcriptome analysis of peripheral blood lymphocytes in pancreatic cancer patients before and after chemotherapy.

Abstract

Abstract Pancreatic Ductal Adenocarcinoma (PDA) is one of the most aggressive malignancies with a 5-year survival rate of 11% due to its high resistance to chemotherapy (CT). Understanding how to better induce an effector response following tumor associated antigen (TAA) stimulation is critical to set up an efficient tailored immunotherapy. Peripheral blood mononuclear cells (PBMC) from PDA patients, before and after gemcitabine-based CT, were in vitrostimulated with four TAA (ENO1, FUBP1, K2C8 and G3P) in presence or absence of immune-check point blockade (ICB). Gemcitabine increased the number of TAA recognized by patient T cells, which positively correlated with survival, a high-rate of TAA-induced proliferative responses and high IFN-γ production. By contrast, ICB suppressed TAA-induced proliferative responses before or after CT. Transcriptional analysis revealed that after CT only, responding patients displayed more differentially expressed genes than non-responding patients, suggesting that Gemcitabine modulates gene expression. The clonotypic analysis of ENO1-stimulated T cells from patients showed that TCRβ repertoire was modulated by CT as some clonotypes. These data indicate that Gemcitabine alone, as opposed to ICB, shifted the immunological tone toward a more effector phenotype. The expansion of V-J rearrangements due to TAA stimulation was enhanced by CT, with a stronger reactivity of precise TAA-specific T cell clones after CT, which support the development of precision immunotherapy in selected patient groups, based on CT combined with TAA vaccination. Supported by grants from AIRC (ID 19931)