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Effect of surgery on pancreatic tumor-dependent lymphocyte asset: modulation of natural killer cell frequency and cytotoxic function.

Iannone F, Porzia A, Peruzzi G, Birarelli P, Milana B, Sacco L, Dinatale G, Peparini N, Prezioso G, Battella S, Caronna R, Morrone S, Palmieri G, Mainiero F, Chirletti P - Pancreas (2015)

Bottom Line: Tumor burden and invasiveness establish a microenvironment that surgery could alter.This study shows a comprehensive analysis of size, dynamics, and function of peripheral lymphocyte subsets in pancreatic cancer patients before and at different times after duodenopancreatectomy.The NK cell functional ability is altered in presurgery patients; duodenopancreatectomy is associated with short-term impairment of NK function and with a long-term NK cell augmentation and reversion of the aberrant NK behavior, which may impact on immunosurveillance against residual cancer.

View Article: PubMed Central - PubMed

Affiliation: From the *Section of Interdisciplinary Surgery F. Durante, Department of Surgical Sciences, †Department of Molecular Medicine, ‡Istituto Italiano di Tecnologia, CLNS, and §Department of Experimental Medicine, Sapienza University of Rome, Italy.

ABSTRACT

Objectives: Tumor burden and invasiveness establish a microenvironment that surgery could alter. This study shows a comprehensive analysis of size, dynamics, and function of peripheral lymphocyte subsets in pancreatic cancer patients before and at different times after duodenopancreatectomy.

Methods: Lymphocyte frequency and natural cytotoxicity were evaluated by flow cytometry and in vitro assay on peripheral blood from initial and advanced-stage pancreatic cancer patients before (BS), at day 7 (PS7), and at day 30 (PS30) after surgery.

Results: An increase in natural killer (NK) cells and the diminution of B-cells occurred at PS30, whereas cytotoxicity decreased at PS7. The positive correlation between NK frequency and cytotoxicity at BS and PS7 revealed an altered NK behavior. The elevation of NK cell frequency at PS30, an initial defect in CD56bright NK, and the aberrant correlation between NK frequency and cytotoxicity remained significant in advanced-stage patients, whereas the diminution of NK cytotoxicity only affected initial stage patients.

Conclusions: The NK cell functional ability is altered in presurgery patients; duodenopancreatectomy is associated with short-term impairment of NK function and with a long-term NK cell augmentation and reversion of the aberrant NK behavior, which may impact on immunosurveillance against residual cancer.

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Distinct alterations in the dynamics of NK cell compartment of initial and advanced-stage cancer patients, at presurgery and postsurgery. Frequency of NK cells (A and D) and percentage of cytotoxicity (B and F) in PB of initial (A and B) and advanced (D and F) cancer stage patients, before surgery (BS), at day 7 (PS7), and at day 30 (PS30) postsurgery, as well as age-matched controls. Bars show median and interquartile range. Scatter plots representing the percentage of cytotoxicity versus the NK cell frequency of each initial (C) and advanced (G) cancer stage patient, before surgery (BS, black symbols and line), at day 7 (PS7, gray symbols and line), and at day 30 (PS30, white symbols) postsurgery, as well as age-matched controls (x symbols). Lines in the plots represent the linear regression for any given pair of variables. *P < 0.05, **P < 0.005, ***P < 0.0001. Distribution and median of NK cell frequency at PS30 in 2-year survivors (black circles) and deceased (white circles) patients, compared with the median of all advanced-stage patients (E, dashed line).
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Figure 3: Distinct alterations in the dynamics of NK cell compartment of initial and advanced-stage cancer patients, at presurgery and postsurgery. Frequency of NK cells (A and D) and percentage of cytotoxicity (B and F) in PB of initial (A and B) and advanced (D and F) cancer stage patients, before surgery (BS), at day 7 (PS7), and at day 30 (PS30) postsurgery, as well as age-matched controls. Bars show median and interquartile range. Scatter plots representing the percentage of cytotoxicity versus the NK cell frequency of each initial (C) and advanced (G) cancer stage patient, before surgery (BS, black symbols and line), at day 7 (PS7, gray symbols and line), and at day 30 (PS30, white symbols) postsurgery, as well as age-matched controls (x symbols). Lines in the plots represent the linear regression for any given pair of variables. *P < 0.05, **P < 0.005, ***P < 0.0001. Distribution and median of NK cell frequency at PS30 in 2-year survivors (black circles) and deceased (white circles) patients, compared with the median of all advanced-stage patients (E, dashed line).

Mentions: Tumor burden and invasiveness may impact on the immune system of the host. Our data reveal a complex defect in NK cell frequency and lytic capability in pancreatic tumor patients. We asked whether the NK cell frequency, PBMC cytotoxic activity, and the correlation between the 2 were influenced by tumor stage (initial vs advanced, according to the Union for International Cancer Control TNM 2009 Classification of Malignant Tumors, Seventh Edition).30 Interestingly, the significant elevation of NK cell frequency at 30 days after surgery was more markedly observed in advanced-stage patients, with respect either to presurgery time point and to controls (Figs. 3A, D); in this context, survivors at 2 years presented a higher median value than deceased ones (Fig. 3E); differently, a transient diminution of NK cytotoxicity at day 7 postsurgery only affected early-stage patients (Figs. 3B, F). Accordingly, NK cell percentage and the extent of PBMC cytotoxicity significantly correlated only in advanced but not in early-stage patients, at presurgery and day 7 postsurgery time points (Figs. 3C, G). Collectively taken, these data suggest that NK cell frequency alteration, and its aberrant correlation with individual patient cytotoxic activity, more deeply affect patients with advanced-stage tumor; conversely, the transient diminution of PBMC cytotoxicity at an early time point after surgery distinctly characterizes patients with early-stage tumor.


Effect of surgery on pancreatic tumor-dependent lymphocyte asset: modulation of natural killer cell frequency and cytotoxic function.

Iannone F, Porzia A, Peruzzi G, Birarelli P, Milana B, Sacco L, Dinatale G, Peparini N, Prezioso G, Battella S, Caronna R, Morrone S, Palmieri G, Mainiero F, Chirletti P - Pancreas (2015)

Distinct alterations in the dynamics of NK cell compartment of initial and advanced-stage cancer patients, at presurgery and postsurgery. Frequency of NK cells (A and D) and percentage of cytotoxicity (B and F) in PB of initial (A and B) and advanced (D and F) cancer stage patients, before surgery (BS), at day 7 (PS7), and at day 30 (PS30) postsurgery, as well as age-matched controls. Bars show median and interquartile range. Scatter plots representing the percentage of cytotoxicity versus the NK cell frequency of each initial (C) and advanced (G) cancer stage patient, before surgery (BS, black symbols and line), at day 7 (PS7, gray symbols and line), and at day 30 (PS30, white symbols) postsurgery, as well as age-matched controls (x symbols). Lines in the plots represent the linear regression for any given pair of variables. *P < 0.05, **P < 0.005, ***P < 0.0001. Distribution and median of NK cell frequency at PS30 in 2-year survivors (black circles) and deceased (white circles) patients, compared with the median of all advanced-stage patients (E, dashed line).
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Related In: Results  -  Collection

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Figure 3: Distinct alterations in the dynamics of NK cell compartment of initial and advanced-stage cancer patients, at presurgery and postsurgery. Frequency of NK cells (A and D) and percentage of cytotoxicity (B and F) in PB of initial (A and B) and advanced (D and F) cancer stage patients, before surgery (BS), at day 7 (PS7), and at day 30 (PS30) postsurgery, as well as age-matched controls. Bars show median and interquartile range. Scatter plots representing the percentage of cytotoxicity versus the NK cell frequency of each initial (C) and advanced (G) cancer stage patient, before surgery (BS, black symbols and line), at day 7 (PS7, gray symbols and line), and at day 30 (PS30, white symbols) postsurgery, as well as age-matched controls (x symbols). Lines in the plots represent the linear regression for any given pair of variables. *P < 0.05, **P < 0.005, ***P < 0.0001. Distribution and median of NK cell frequency at PS30 in 2-year survivors (black circles) and deceased (white circles) patients, compared with the median of all advanced-stage patients (E, dashed line).
Mentions: Tumor burden and invasiveness may impact on the immune system of the host. Our data reveal a complex defect in NK cell frequency and lytic capability in pancreatic tumor patients. We asked whether the NK cell frequency, PBMC cytotoxic activity, and the correlation between the 2 were influenced by tumor stage (initial vs advanced, according to the Union for International Cancer Control TNM 2009 Classification of Malignant Tumors, Seventh Edition).30 Interestingly, the significant elevation of NK cell frequency at 30 days after surgery was more markedly observed in advanced-stage patients, with respect either to presurgery time point and to controls (Figs. 3A, D); in this context, survivors at 2 years presented a higher median value than deceased ones (Fig. 3E); differently, a transient diminution of NK cytotoxicity at day 7 postsurgery only affected early-stage patients (Figs. 3B, F). Accordingly, NK cell percentage and the extent of PBMC cytotoxicity significantly correlated only in advanced but not in early-stage patients, at presurgery and day 7 postsurgery time points (Figs. 3C, G). Collectively taken, these data suggest that NK cell frequency alteration, and its aberrant correlation with individual patient cytotoxic activity, more deeply affect patients with advanced-stage tumor; conversely, the transient diminution of PBMC cytotoxicity at an early time point after surgery distinctly characterizes patients with early-stage tumor.

Bottom Line: Tumor burden and invasiveness establish a microenvironment that surgery could alter.This study shows a comprehensive analysis of size, dynamics, and function of peripheral lymphocyte subsets in pancreatic cancer patients before and at different times after duodenopancreatectomy.The NK cell functional ability is altered in presurgery patients; duodenopancreatectomy is associated with short-term impairment of NK function and with a long-term NK cell augmentation and reversion of the aberrant NK behavior, which may impact on immunosurveillance against residual cancer.

View Article: PubMed Central - PubMed

Affiliation: From the *Section of Interdisciplinary Surgery F. Durante, Department of Surgical Sciences, †Department of Molecular Medicine, ‡Istituto Italiano di Tecnologia, CLNS, and §Department of Experimental Medicine, Sapienza University of Rome, Italy.

ABSTRACT

Objectives: Tumor burden and invasiveness establish a microenvironment that surgery could alter. This study shows a comprehensive analysis of size, dynamics, and function of peripheral lymphocyte subsets in pancreatic cancer patients before and at different times after duodenopancreatectomy.

Methods: Lymphocyte frequency and natural cytotoxicity were evaluated by flow cytometry and in vitro assay on peripheral blood from initial and advanced-stage pancreatic cancer patients before (BS), at day 7 (PS7), and at day 30 (PS30) after surgery.

Results: An increase in natural killer (NK) cells and the diminution of B-cells occurred at PS30, whereas cytotoxicity decreased at PS7. The positive correlation between NK frequency and cytotoxicity at BS and PS7 revealed an altered NK behavior. The elevation of NK cell frequency at PS30, an initial defect in CD56bright NK, and the aberrant correlation between NK frequency and cytotoxicity remained significant in advanced-stage patients, whereas the diminution of NK cytotoxicity only affected initial stage patients.

Conclusions: The NK cell functional ability is altered in presurgery patients; duodenopancreatectomy is associated with short-term impairment of NK function and with a long-term NK cell augmentation and reversion of the aberrant NK behavior, which may impact on immunosurveillance against residual cancer.

Show MeSH
Related in: MedlinePlus