Impact of surgery and chemotherapy on cellular immunity in pancreatic carcinoma patients in view of an integration of standard cancer treatment with immunotherapy.
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.
Department of Clinical Physiopathology, University of Turin, Turin, Italy. graziella.bellone@unito.it
Graziella
G
Bellone
Anna
A
Novarino
Barbara
B
Vizio
Gabriele
G
Brondino
Alfredo
A
Addeo
Adriana
A
Prati
Alice
A
Giacobino
Donata
D
Campra
Gian Ruggero
GR
Fronda
Libero
L
Ciuffreda
D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology* / Q000601:surgery; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005434:Flow Cytometry; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000276:immunology / Q000378:metabolism; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000601:surgery; D010534:Peritoneal Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D010865:Pilot Projects; D011379:Prognosis; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome; D000093542:Gemcitabine
D017252:CD3 Complex; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D003841:Deoxycytidine; D007371:Interferon-gamma; D002945:Cisplatin; D005472:Fluorouracil; D000093542:Gemcitabine