title: Cancer-initiating cells from colorectal cancer patients escape from T cell-mediated immunosurveillance in vitro through membrane-bound IL-4.
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.
authors.affiliation: Unit of Immuno-Biotherapy of Melanoma and Solid Tumors, San Raffaele Foundation Centre, 20132 Milan, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: Volonté
authors.forename: Tiziano
authors.initials: T
authors.lastname: Di Tomaso
authors.forename: Michela
authors.initials: M
authors.lastname: Spinelli
authors.forename: Matilde
authors.initials: M
authors.lastname: Todaro
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanvito
authors.forename: Luca
authors.initials: L
authors.lastname: Albarello
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Bissolati
authors.forename: Luca
authors.initials: L
authors.lastname: Ghirardelli
authors.forename: Elena
authors.initials: E
authors.lastname: Orsenigo
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.forename: Giorgio
authors.initials: G
authors.lastname: Stassi
authors.forename: Paolo
authors.initials: P
authors.lastname: Dellabona
authors.forename: Carlo
authors.initials: C
authors.lastname: Staudacher
authors.forename: Giorgio
authors.initials: G
authors.lastname: Parmiani
authors.forename: Cristina
authors.initials: C
authors.lastname: Maccalli
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007157:Immunologic Surveillance / Q000276:immunology*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000378:metabolism*; D018874:Spheroids, Cellular; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; C479798:colorectal tumor-associated antigen, human; D015847:Interleukin-4