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

Abstract

Abstract.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 51 Cr-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 apoptosisprone 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-Á 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 IL12p70 release by PBMC rose concomitantly with the anti-CD3 stimulated-IFN-Á 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.

A new pharmacological approach to gastrointestinal cancer at high risk of relapse based on maintenance of the cytostatic effect

“…As to its immunomodulatory effects, no immunosuppressive activity has been reported. Rather, in combined treatment, the antitumor immunity benefits are produced by inducing lymphocytosis [44], increased CD4+ and LAK cell numbers and cytotoxicity with a marked reduction of Tregs, and a noteworthy infiltration of CD8+ T cells [45,46]. Efficient CTL and NK cell-mediated killing, even at concentrations comparable with the maximally achieved therapeutic concentrations in humans, were found [47,48].…”

Cascading Adoptive Cell Therapy for Metastatic Melanoma

“…18,19 It is clinically accepted that major surgery suppresses cell mediated immunity (CMI) for several days and that more invasive procedures lead to deeper and longer immunosuppression. 20 Several mechanisms might promote postoperative metastasis. First, general anesthesia has been shown in clinical studies to suppress CMI, 21 and regional anesthesia; however, it often blocks immunosuppression.…”

Effect of Surgery on Pancreatic Tumor-Dependent Lymphocyte Asset

“…Surgery can induce a rapid and transient inflammatory status and also modify, both locally and systemically, immune cell distribution and/or activation and release of soluble factors 27 ; this results in a long-lasting alteration of patient’s immune system and, ultimately, of immunosurveillance. 28,29 …”