IL-21 Enhances Natural Killer Cell Response to Cetuximab-Coated Pancreatic Tumor Cells
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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 assess ADCC, 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 cetuximab-coated 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. Clin Cancer Res; 23(2); 489–502. ©2016 AACR.
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IL-21 and IL-15 have been proposed to strongly enhance NK cell-mediated immunity against cancer cells.
“The cytokines IL-21 and IL-15 have been suggested to substantially boost NK cell-mediated immunity against cancer cells222–225.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [222]
The Discussion (page unavailable) reports that IL-21 enhanced NK-cell elimination of cetuximab-coated tumor cells, supporting the IL-21 part of the claim. The Introduction notes that NK cells have IL-15 receptors, and the Discussion mentions a mouse study comparing IL-15 with IL-21, but neither passage establishes that IL-15 substantially boosts NK-cell-mediated immunity against cancer cells. (LLM, conf=0.85)
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- Authors
- McMichael, E. L., Jaime-Ramirez, A. C., Guenterberg, K. D., Luedke, E., Atwal, L. S., Campbell, A. R., Hu, Z., Tatum, A. S., Kondadasula, S. V., Mo, X., Tridandapani, S., Bloomston, M., Ellison, E. C., Williams, T. M., Bekaii-Saab, T., & Carson, W. E.
- Affiliations
- The Ohio State University (US)
- 2Department of Neurosurgery, The Ohio State University, Columbus, Ohio.
- 8Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
- Corresponding author
- Carson, William E.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2017-01-15
- Volume
- 23
- Issue
- 2
- Pages
- 489-502
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC5241232
- OpenAlex
- W2490014226
- Cited by
- 70
- References
- 56
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 8 · 2023: 11 · 2022: 6 · 2021: 6 · 2020: 10 · 2019: 5 · 2018: 4 · 2017: 7
- FWCI
- 3.23
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Clinical Cancer Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (P01 CA095426 and P30 CA016058, CA84402, K24 CA93670, T32 GM068412, T32 CA009338)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- IL-21, natural killer cells, cetuximab, pancreatic cancer, EGFR inhibition, antibody-dependent cellular cytotoxicity, KRAS mutation, interferon-gamma, T cell chemotaxis, STAT1 signaling, ERK signaling, gemcitabine combination therapy, tumor xenografts
- MeSH terms
- Cetuximab, Interleukin-21, Animals, Antibody-Dependent Cell Cytotoxicity, Chemotaxis, Flow Cytometry, Humans, Interferon-gamma, Interleukins, Killer Cells, Natural, Lymphocyte Activation, Pancreatic Neoplasms, T-Lymphocytes, Proto-Oncogene Proteins p21(ras), Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice
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