Cancer-initiating cells from colorectal cancer patients escape from T cell-mediated immunosurveillance in vitro through membrane-bound IL-4

Andrea Volonté, Tiziano Di Tomaso, Michela Spinelli, Matilde Todaro, Francesca Sanvito, Luca Albarello, Massimiliano Bissolati, Luca Ghirardelli, Elena Orsenigo, Soldano Ferrone, Claudio Doglioni, Giorgio Stassi, Paolo Dellabona, Carlo Staudacher, Giorgio Parmiani, Cristina MacCalli

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Abstract

Cancer-initiating cells (CICs) that are responsible for tumor initiation, propagation, and resistance to standard therapies have been isolated from human solid tumors, including colorectal cancer (CRC). The aim of this study was to obtain an immunological profile of CRC-derived CICs and to identify CIC-associated target molecules for T cell immunotherapy. We have isolated cells with CIC properties along with their putative non-CIC autologous counterparts from human primary CRC tissues. These CICs have been shown to display "tumor-initiating/stemness" properties, including the expression of CIC-associated markers (e.g., CD44, CD24, ALDH-1, EpCAM, Lgr5), multipotency, and tumorigenicity following injection in immunodeficient mice. The immune profile of these cells was assessed by phenotype analysis and by in vitro stimulation of PBMCs with CICs as a source of Ags. CICs, compared with non-CIC counterparts, showed weak immunogenicity. This feature correlated with the expression of high levels of immunomodulatory molecules, such as IL-4, and with CIC-mediated inhibitory activity for anti-tumor T cell responses. CIC-associated IL-4 was found to be responsible for this negative function, which requires cell-to-cell contact with T lymphocytes and which is impaired by blocking IL-4 signaling. In addition, the CRC-associated Ag COA-1 was found to be expressed by CICs and to represent, in an autologous setting, a target molecule for anti-tumor T cells. Our study provides relevant information that may contribute to designing new immunotherapy protocols to target CICs in CRC patients. The Journal of Immunology, 2014, 192: 523-532.

Original languageEnglish
Pages (from-to)523-532
Number of pages10
JournalJournal of Immunology
Volume192
Issue number1
DOIs
Publication statusPublished - Jan 1 2014

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ASJC Scopus subject areas

  • Immunology

Cite this

Volonté, A., Di Tomaso, T., Spinelli, M., Todaro, M., Sanvito, F., Albarello, L., Bissolati, M., Ghirardelli, L., Orsenigo, E., Ferrone, S., Doglioni, C., Stassi, G., Dellabona, P., Staudacher, C., Parmiani, G., & MacCalli, C. (2014). Cancer-initiating cells from colorectal cancer patients escape from T cell-mediated immunosurveillance in vitro through membrane-bound IL-4. Journal of Immunology, 192(1), 523-532. https://doi.org/10.4049/jimmunol.1301342