Impact of surgery and chemotherapy on cellular immunity in pancreatic carcinoma patients in view of an integration of standard cancer treatment with immunotherapy

• Published in: International journal of oncology Vol. 34; no. 6; pp. 1701 - 1715
• Main Authors: BELLONE, Graziella, NOVARINO, Anna, VIZIO, Barbara, BRONDINO, Gabriele, ADDEO, Alfredo, PRATI, Adriana, GIACOBINO, Alice, CAMPRA, Donata, RUGGERO FRONDA, Gian, CIUFFREDA, Libero
• Format: Journal Article
• Language: English
• Published: Athens Editorial Academy of the International Journal of Oncology 01.06.2009
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - immunology; Adenocarcinoma - surgery; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; CD3 Complex - immunology; CD3 Complex - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cisplatin - administration & dosage; Combined Modality Therapy; Cytotoxicity, Immunologic; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Female; Flow Cytometry; Fluorouracil - administration & dosage; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Immunotherapy; Interferon-gamma - metabolism; Interleukin-12 Subunit p40 - immunology; Interleukin-12 Subunit p40 - metabolism; Killer Cells, Lymphokine-Activated - drug effects; Killer Cells, Lymphokine-Activated - immunology; Killer Cells, Lymphokine-Activated - metabolism; Lipopolysaccharides - pharmacology; Liver Neoplasms - immunology; Liver Neoplasms - secondary; Liver Neoplasms - therapy; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Lung Neoplasms - immunology; Lung Neoplasms - secondary; Lung Neoplasms - therapy; Lymphocyte Activation; Male; Medical sciences; Middle Aged; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - surgery; Peritoneal Neoplasms - immunology; Peritoneal Neoplasms - secondary; Peritoneal Neoplasms - therapy; Pilot Projects; Prognosis; Survival Rate; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Treatment Outcome; Tumors; Human; Integration; Immune response; Cellular immunity; tumor immunity; Malignant tumor; Standards; Chemotherapy; Cancerology; Treatment; pancreatic carcinoma; Surgery; Immunotherapy; Pancreas cancer; Digestive diseases; Cancer; Pancreatic disease; Pancreas carcinoma
• ISSN: 1019-6439
• DOI: 10.3892/ijo_00000301

As surgery and chemotherapy may act as adjuvants providing antitumor immunity benefits, we ran phenotypical and functional immunomonitoring in patients with resectable pancreatic adenocarcinoma and advanced metastatic disease receiving combined treatment (cisplatin, gemcitabine, 5-FU). Blood was taken before/one month after resection; before/during chemotherapy. Controls were age- and gender-matched. Circulating lymphocyte, myeloid and plasmacytoid dendritic cell (MDC and PDC) subsets were examined by flow cytometry; functional activity by mixed lymphocyte reaction (MLR) for DC allostimulation, through 4-h 51Cr-release assay for Natural Killer (NK) and lymphokine-activated-killer (LAK) cell cytotoxicity; ELISA for spontaneous/activated cytokine release by PBMC and T cells. Significant differences occurred in several parameters between pretreatment patient and control values: fewer CD8+ cells and increased apoptosis-prone CD3+/CD95+ lymphocytes, higher frequency of MDC, reduced allostimulatory activity by ex vivo-generated DC, depressed LAK activity, elevated IL-10 and IL-12p40 production; impaired IL-12p70 and IFN-gamma production by stimulated PBMC and T cells. Only IL-12p70 level was correlated with survival. One month after radical, but not palliative surgery, the percentage of T-lymphocytes coexpressing CD3/CD95 decreased significantly, the stimulatory capacity of DC increased, and LPS-induced IL-12p70 release by PBMC rose concomitantly with the anti-CD3 stimulated-IFN-gamma production by T cells. In patients with locally advanced or metastatic disease, one and/or two combined drug cycles increased percentage of CD4+ cells and LAK cell cytotoxicity and decreased PDC frequency and spontaneous/LPS-stimulated IL-10 by PBMC. Results suggest immunological changes induced by surgical resection/combined chemotherapy indicate specific precisely-timed windows of opportunity for introducing immunotherapy in pancreatic cancer, possibly improving survival in this highly lethal disease.