Targeting the Epidermal Growth Factor Receptor Can Counteract the Inhibition of Natural Killer Cell Function Exerted by Colorectal Tumor-Associated Fibroblasts

Delfina Costa, Roberta Venè, Roberto Benelli, Emanuele Romairone, Stefano Scabini, Silvia Catellani, Barbara Rebesco, Luca Mastracci, Federica Grillo, Simona Minghelli, Fabrizio Loiacono, Maria Raffaella Zocchi, Alessandro Poggi

Research output: Contribution to journalArticle

Abstract

Mesenchymal stromal cells (MSC) present in the tumor microenvironment [usually named tumor-associated fibroblasts (TAF)] can exert immunosuppressive effects on T and natural killer (NK) lymphocytes, favoring tumor immune escape. We have analyzed this mechanism in colorectal carcinoma (CRC) and found that co-culture of NK cells with TAF can prevent the IL-2-mediated NKG2D upregulation. This leads to the impairment of NKG2D-mediated recognition of CRC cells, sparing the NK cell activation through DNAM1 or FcγRIIIA (CD16). In situ, TAF express detectable levels of epidermal growth factor receptor (EGFR); thus, the therapeutic anti-EGFR humanized antibody cetuximab can trigger the antibody-dependent cellular cytotoxicity of TAF, through the engagement of FcγRIIIA on NK cells. Importantly, in the tumor, we found a lymphoid infiltrate containing NKp46+CD3- NK cells, enriched in CD16+ cells. This population, sorted and cultured with IL-2, could be triggered via CD16 and via NKG2D. Of note, ex vivo NKp46+CD3- cells were able to kill autologous TAF; in vivo, this might represent a control mechanism to reduce TAF-mediated regulatory effect on NK cell function. Altogether, these findings suggest that MSC from the neoplastic mucosa (TAF) of CRC patients can downregulate the immune cell recognition of CRC tumor cells. This immunosuppression can be relieved by the anti-EGFR antibody used in CRC immunotherapy.

Original languageEnglish
Pages (from-to)1150
JournalFrontiers in Immunology
Volume9
DOIs
Publication statusPublished - 2018

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Epidermal Growth Factor Receptor
Natural Killer Cells
Colorectal Neoplasms
Mesenchymal Stromal Cells
Interleukin-2
Tumor Escape
Antibodies, Monoclonal, Humanized
Tumor Microenvironment
Antibodies
Immunosuppressive Agents
Coculture Techniques
Cancer-Associated Fibroblasts
Immunotherapy
Immunosuppression
Mucous Membrane
Up-Regulation
Down-Regulation
Lymphocytes
Population
Neoplasms

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Targeting the Epidermal Growth Factor Receptor Can Counteract the Inhibition of Natural Killer Cell Function Exerted by Colorectal Tumor-Associated Fibroblasts. / Costa, Delfina; Venè, Roberta; Benelli, Roberto; Romairone, Emanuele; Scabini, Stefano; Catellani, Silvia; Rebesco, Barbara; Mastracci, Luca; Grillo, Federica; Minghelli, Simona; Loiacono, Fabrizio; Zocchi, Maria Raffaella; Poggi, Alessandro.

In: Frontiers in Immunology, Vol. 9, 2018, p. 1150.

Research output: Contribution to journalArticle

Costa, D, Venè, R, Benelli, R, Romairone, E, Scabini, S, Catellani, S, Rebesco, B, Mastracci, L, Grillo, F, Minghelli, S, Loiacono, F, Zocchi, MR & Poggi, A 2018, 'Targeting the Epidermal Growth Factor Receptor Can Counteract the Inhibition of Natural Killer Cell Function Exerted by Colorectal Tumor-Associated Fibroblasts', Frontiers in Immunology, vol. 9, pp. 1150. https://doi.org/10.3389/fimmu.2018.01150
Costa, Delfina ; Venè, Roberta ; Benelli, Roberto ; Romairone, Emanuele ; Scabini, Stefano ; Catellani, Silvia ; Rebesco, Barbara ; Mastracci, Luca ; Grillo, Federica ; Minghelli, Simona ; Loiacono, Fabrizio ; Zocchi, Maria Raffaella ; Poggi, Alessandro. / Targeting the Epidermal Growth Factor Receptor Can Counteract the Inhibition of Natural Killer Cell Function Exerted by Colorectal Tumor-Associated Fibroblasts. In: Frontiers in Immunology. 2018 ; Vol. 9. pp. 1150.
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AU - Venè, Roberta

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AU - Romairone, Emanuele

AU - Scabini, Stefano

AU - Catellani, Silvia

AU - Rebesco, Barbara

AU - Mastracci, Luca

AU - Grillo, Federica

AU - Minghelli, Simona

AU - Loiacono, Fabrizio

AU - Zocchi, Maria Raffaella

AU - Poggi, Alessandro

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AB - Mesenchymal stromal cells (MSC) present in the tumor microenvironment [usually named tumor-associated fibroblasts (TAF)] can exert immunosuppressive effects on T and natural killer (NK) lymphocytes, favoring tumor immune escape. We have analyzed this mechanism in colorectal carcinoma (CRC) and found that co-culture of NK cells with TAF can prevent the IL-2-mediated NKG2D upregulation. This leads to the impairment of NKG2D-mediated recognition of CRC cells, sparing the NK cell activation through DNAM1 or FcγRIIIA (CD16). In situ, TAF express detectable levels of epidermal growth factor receptor (EGFR); thus, the therapeutic anti-EGFR humanized antibody cetuximab can trigger the antibody-dependent cellular cytotoxicity of TAF, through the engagement of FcγRIIIA on NK cells. Importantly, in the tumor, we found a lymphoid infiltrate containing NKp46+CD3- NK cells, enriched in CD16+ cells. This population, sorted and cultured with IL-2, could be triggered via CD16 and via NKG2D. Of note, ex vivo NKp46+CD3- cells were able to kill autologous TAF; in vivo, this might represent a control mechanism to reduce TAF-mediated regulatory effect on NK cell function. Altogether, these findings suggest that MSC from the neoplastic mucosa (TAF) of CRC patients can downregulate the immune cell recognition of CRC tumor cells. This immunosuppression can be relieved by the anti-EGFR antibody used in CRC immunotherapy.

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