ABSTRACT
PURPOSE: This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome. RESULTS: Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively. CONCLUSIONS: Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Pancreatic Ductal/drug therapy , Immune Checkpoint Proteins/drug effects , Pancreatic Neoplasms/drug therapy , T-Lymphocytes, Regulatory/drug effects , Aged , Albumins/therapeutic use , CD4-Positive T-Lymphocytes/chemistry , CD4-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/chemistry , CD8-Positive T-Lymphocytes/drug effects , Carcinoma, Pancreatic Ductal/immunology , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Female , Fluorouracil/therapeutic use , Forkhead Transcription Factors , Hepatitis A Virus Cellular Receptor 2/analysis , Humans , Immune Checkpoint Proteins/analysis , Irinotecan/therapeutic use , Leucovorin/therapeutic use , Male , Middle Aged , Oxaliplatin/therapeutic use , Paclitaxel/therapeutic use , Pancreatic Neoplasms/immunology , Pilot Projects , Programmed Cell Death 1 Receptor/analysis , Programmed Cell Death 1 Receptor/drug effects , Progression-Free Survival , Prospective Studies , T-Lymphocytes, Regulatory/chemistry , GemcitabineABSTRACT
BACKGROUND: Neuronal signaling has been implicated in the pathophysiology of multiple malignancies. In biliary tract cancers (BTCs), tumor cell expression of nerve growth factor (NGF) and its receptor neurotrophic tropomyosin receptor kinase (NTRK) has been reported in Asian patients and linked to inferior clinical outcome. Furthermore, NTRK fusions have emerged as a promising target in various cancers. Expression patterns of these markers in Caucasian patients remain unknown. METHODS: In this study, 106 patients with BTCs were included. Immunohistochemistry for pan-NTRK and NGF-beta was performed on > 90 samples of this cohort. Additionally, samples from two independent cohorts, incorporating 254 cases, were used to confirm the findings of the original cohort. RESULTS: While expression of pan-NTRK and NGF-beta was readily detectable in peri-tumoral nerves, these markers were not detectable in malignant epithelial cells in our cohort. CONCLUSIONS: In a large cohort of Caucasian patients with BTC, NTRK and NGF-beta were not detectable, underscoring potential differences between Caucasian and Asian patient populations.