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Front. Immunol. | doi: 10.3389/fimmu.2018.01150

Targeting the epidermal growth factor receptor can counteract the inhibition of natural killer cell function exerted by colorectal tumor-associated fibroblasts

Delfina Costa1, Roberta Venè1, Roberto Benelli2, Silvia Catellani3, Stefano Scabini4, Emanuele Romairone4, Barbara Rebesco5,  Luca Mastracci6, Federica Grillo6, Simona Minghelli7,  Fabrizio Loiacono8,  Maria Raffaella Zocchi9 and  Alessandro Poggi1*
  • 1Terapie Oncologiche Integrate, Ospedale San Martino (IRCCS), Italy
  • 2Terapie Oncologiche Integrate, Ospedale San Martino (IRCCS), Italy
  • 3Terapie Oncologiche Integrate, Ospedale San Martino (IRCCS), Italy
  • 4Chirurgia Gnerale, Specialistica ed Oncologica, Ospedale San Martino (IRCCS), Italy
  • 5Direzione Sanitaria, Ospedale San Martino (IRCCS), Italy
  • 6Dipartimento della Diagnostica, della Patologia e delle Cure ad Alta complessità Tecnologica, Ospedale San Martino (IRCCS), Italy
  • 7Istituto Giannina Gaslini (IRCCS), Italy
  • 8Terapie Oncologiche Integrate, Ospedale San Martino (IRCCS), Italy
  • 9Division of of Immunology, Transplants and Infectious Diseases, San Raffaele Scientific Institute (IRCCS), Italy

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, favouring 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 IL2-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 IL2, 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 down-regulate the immune cell recognition of CRC tumor cells. This immunosuppression can be relieved by the anti-EGFR antibody used in CRC immunotherapy.

Keywords: CRC, NKG2D, NK cells, EGFR, ADCC, cetuximab

Received: 07 Dec 2017; Accepted: 07 May 2018.

Edited by:

Anahid Jewett, University of California, Los Angeles, United States

Reviewed by:

Subramaniam Malarkannan, Medical College of Wisconsin, United States
Daniel Olive, Faculté de Médecine, Aix Marseille Université, France  

Copyright: © 2018 Costa, Venè, Benelli, Catellani, Scabini, Romairone, Rebesco, Mastracci, Grillo, Minghelli, Loiacono, Zocchi and Poggi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD, PhD. Alessandro Poggi, Ospedale San Martino (IRCCS), Terapie Oncologiche Integrate, Largo Rosanna benzi 10, Padiglione 90 CBA/IST-Nord piano C4, Genoa, 16132, Italia, Italy,