IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells

Elizabeth L. McMichael, Alena Cristina Jaime-Ramirez, Kristan D. Guenterberg, Eric Luedke, Lakhvir S. Atwal, Amanda R. Campbell, Zhiwei Hu, Armika S. Tatum, Sri Vidya Kondadasula, Xiaokui Mo, Susheela Tridandapani, Mark Bloomston, E. Christopher Ellison, Terence M. Williams, Tanios Bekaii-Saab, William E. Carson

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Purpose: Alternative strategies to EGFR blockage by mAbs is necessary to improve the efficacy of therapy in patients with locally advanced or metastatic pancreatic cancer. One such strategy includes the use of NK cells to clear cetuximab-coated tumor cells, as need for novel therapeutic approaches to enhance the efficacy of cetuximab is evident. We show that IL-21 enhances NK cell-mediated effector functions against cetuximab-coated pancreatic tumor cells irrespective of KRAS mutation status. Experimental Design: NK cells from normal donors or donors with pancreatic cancer were used to assessADCC, IFN-γ release, and T-cell chemotaxis toward human pancreatic cancer cell lines. The in vivo efficacy of IL-21 in combination with cetuximab was evaluated in a subcutaneous and intraperitoneal model of pancreatic cancer. Results: NK cell lysis of cetuximab-coated wild-type and mutant kras pancreatic cancer cell lines were significantly higher following NK cell IL-21 treatment. In response to cetuximabcoated pancreatic tumor cells, IL-21-treated NK cells secreted significantly higher levels of IFN-γ and chemokines, increased chemotaxis of T cells, and enhanced NK cell signal transduction via activation of ERK and STAT1. Treatment of mice bearing subcutaneous or intraperitoneal EGFR-positive pancreatic tumor xenografts with mIL-21 and cetuximab led to significant inhibition of tumor growth, a result further enhanced by the addition of gemcitabine. Conclusions: These results suggest that cetuximab treatment in combination with IL-21 adjuvant therapy in patients with EGFR-positive pancreatic cancer results in significant NK cell activation, irrespective of KRAS mutation status, and may be a potential therapeutic strategy.

Original languageEnglish (US)
Pages (from-to)489-502
Number of pages14
JournalClinical Cancer Research
Volume23
Issue number2
DOIs
StatePublished - Jan 15 2017
Externally publishedYes

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Natural Killer Cells
Pancreatic Neoplasms
Neoplasms
Chemotaxis
gemcitabine
Therapeutics
Tissue Donors
T-Lymphocytes
Cell Line
Mutation
Cetuximab
interleukin-21
Chemokines
Heterografts
Signal Transduction
Research Design
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

McMichael, E. L., Jaime-Ramirez, A. C., Guenterberg, K. D., Luedke, E., Atwal, L. S., Campbell, A. R., ... Carson, W. E. (2017). IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. Clinical Cancer Research, 23(2), 489-502. https://doi.org/10.1158/1078-0432.CCR-16-0004

IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. / McMichael, Elizabeth L.; Jaime-Ramirez, Alena Cristina; Guenterberg, Kristan D.; Luedke, Eric; Atwal, Lakhvir S.; Campbell, Amanda R.; Hu, Zhiwei; Tatum, Armika S.; Kondadasula, Sri Vidya; Mo, Xiaokui; Tridandapani, Susheela; Bloomston, Mark; Ellison, E. Christopher; Williams, Terence M.; Bekaii-Saab, Tanios; Carson, William E.

In: Clinical Cancer Research, Vol. 23, No. 2, 15.01.2017, p. 489-502.

Research output: Contribution to journalArticle

McMichael, EL, Jaime-Ramirez, AC, Guenterberg, KD, Luedke, E, Atwal, LS, Campbell, AR, Hu, Z, Tatum, AS, Kondadasula, SV, Mo, X, Tridandapani, S, Bloomston, M, Ellison, EC, Williams, TM, Bekaii-Saab, T & Carson, WE 2017, 'IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells', Clinical Cancer Research, vol. 23, no. 2, pp. 489-502. https://doi.org/10.1158/1078-0432.CCR-16-0004
McMichael EL, Jaime-Ramirez AC, Guenterberg KD, Luedke E, Atwal LS, Campbell AR et al. IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. Clinical Cancer Research. 2017 Jan 15;23(2):489-502. https://doi.org/10.1158/1078-0432.CCR-16-0004
McMichael, Elizabeth L. ; Jaime-Ramirez, Alena Cristina ; Guenterberg, Kristan D. ; Luedke, Eric ; Atwal, Lakhvir S. ; Campbell, Amanda R. ; Hu, Zhiwei ; Tatum, Armika S. ; Kondadasula, Sri Vidya ; Mo, Xiaokui ; Tridandapani, Susheela ; Bloomston, Mark ; Ellison, E. Christopher ; Williams, Terence M. ; Bekaii-Saab, Tanios ; Carson, William E. / IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 2. pp. 489-502.
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AU - McMichael, Elizabeth L.

AU - Jaime-Ramirez, Alena Cristina

AU - Guenterberg, Kristan D.

AU - Luedke, Eric

AU - Atwal, Lakhvir S.

AU - Campbell, Amanda R.

AU - Hu, Zhiwei

AU - Tatum, Armika S.

AU - Kondadasula, Sri Vidya

AU - Mo, Xiaokui

AU - Tridandapani, Susheela

AU - Bloomston, Mark

AU - Ellison, E. Christopher

AU - Williams, Terence M.

AU - Bekaii-Saab, Tanios

AU - Carson, William E.

PY - 2017/1/15

Y1 - 2017/1/15

N2 - Purpose: Alternative strategies to EGFR blockage by mAbs is necessary to improve the efficacy of therapy in patients with locally advanced or metastatic pancreatic cancer. One such strategy includes the use of NK cells to clear cetuximab-coated tumor cells, as need for novel therapeutic approaches to enhance the efficacy of cetuximab is evident. We show that IL-21 enhances NK cell-mediated effector functions against cetuximab-coated pancreatic tumor cells irrespective of KRAS mutation status. Experimental Design: NK cells from normal donors or donors with pancreatic cancer were used to assessADCC, IFN-γ release, and T-cell chemotaxis toward human pancreatic cancer cell lines. The in vivo efficacy of IL-21 in combination with cetuximab was evaluated in a subcutaneous and intraperitoneal model of pancreatic cancer. Results: NK cell lysis of cetuximab-coated wild-type and mutant kras pancreatic cancer cell lines were significantly higher following NK cell IL-21 treatment. In response to cetuximabcoated pancreatic tumor cells, IL-21-treated NK cells secreted significantly higher levels of IFN-γ and chemokines, increased chemotaxis of T cells, and enhanced NK cell signal transduction via activation of ERK and STAT1. Treatment of mice bearing subcutaneous or intraperitoneal EGFR-positive pancreatic tumor xenografts with mIL-21 and cetuximab led to significant inhibition of tumor growth, a result further enhanced by the addition of gemcitabine. Conclusions: These results suggest that cetuximab treatment in combination with IL-21 adjuvant therapy in patients with EGFR-positive pancreatic cancer results in significant NK cell activation, irrespective of KRAS mutation status, and may be a potential therapeutic strategy.

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