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.

Novel Tumor Antigen-Specific Monoclonal Antibody-Based Immunotherapy to Eradicate Both Differentiated Cancer Cells and Cancer-Initiating Cells in Solid Tumors

“…whether this functional abnormality is caused only by HLA class I APM component downregulation, since it is associated with PD-L1 expression in glioblastoma CICs and with high expression of membrane-bound interleukin-4 in colon CICs. 73,74 Similar results have been reported by Brown and colleagues who used a non-tumor-related cytomegalovirus (CMV) antigen as a model TA. 76 CICs were recognized by cognate T cells only after pulsing with CMV antigen-derived peptide.…”

Concise Review: Targeting Cancer Stem Cells Using Immunologic Approaches

“…Recently Volonté et al reported that CSCs derived from colorectal cancer show weak immunogenicity compared with non‐CSC counterparts. This feature may correlate with the expression of high levels of IL‐4 by the CSCs because neutralization of CSC‐associated IL‐4 can rescue the proliferative activity of T lymphocytes . Based on the results in this study, new immunotherapy protocols to target CSCs might involve blocking inhibitory activity of immunomodulatory molecules as well as activating T cell by CSC specific or associated antigens.…”

Targeting of IL-4 and IL-13 receptors for cancer therapy

“…In this study, cell-to-cell contact was required, as co-cultivation without the cellular contact of T lymphocytes with CICs or with CIC-derived cell culture supernatant did not affect their proliferation. Thus, blocking of IL-4 may affect T cell-mediated tumor activity, which could lead to a skewed immune response toward T cell effector responses [62].…”