Abstract
Colon antigen-1 (COA-1) was recently identified as a novel antigen of colorectal cancer encoded by the UBXD5 gene. Here, we evaluated whether a specific T-cell-mediated response directed against this molecule can occur in colorectal cancer patients. Antigen- and tumor-specific immunologic responses of peripheral blood mononuclear cells (PBMC) stimulated in vitro with the MHC class II-associated immunogenic epitope of COA-1 (FSTFPPTLYQDDTLTLQAAG) were analyzed by IFN-gamma ELISPOT assay. COA-1-specific and tumor-reactive T lymphocytes were isolated from all (n = 7) HLA-DRbeta1*0402+ or *1301+ colorectal cancer patients with progressive disease (Dukes' C and D) but not in patients (n = 4) with early-stage tumor (Dukes' A and B) and in healthy donors (n = 5), suggesting that the immune response against this antigen is associated with the progression of colorectal cancer. COA-1- and tumor-specific T lymphocytes displayed a CD3+CD4+CD69+CD45RA+ phenotype, compatible with the activated effector-type T-cell subset, and most of them exerted cytotoxic activity against HLA-matched and COA-1+ tumor cells. COA-1-specific T cells could also be isolated by in vitro stimulation of peripheral blood mononuclear cells with autologous dendritic cells loaded with tumor lysate, suggesting that this antigen can generate a dominant immunologic response against colorectal cancer cells. Notably, we could identify also COA-1-derived epitopes binding to HLA-A*0201 molecules that elicited antigen- and tumor-specific CD8+ T-cell-mediated responses in colorectal cancer patients. Both CD4+ and CD8+ T-cell responses against COA-1 can occur in colorectal cancer patients with metastatic disease, suggesting that this antigen is suitable for immunotherapeutic protocols of these patients.
Highlights
Experimental Design: Antigen- and tumor-specific immunologic responses of peripheral blood mononuclear cells (PBMC) stimulated in vitro with the MHC class II-associated immunogenic epitope of Colon antigen-1 (COA-1) (FSTFPPTLYQDDTLTLQAAG) were analyzed by IFN-g ELISPOTassay
We showed that COA-1-specific and tumor-directed CD4+ T lymphocytes could be isolated from patients with metastatic but not with early disease, whereas antigen-specific T cells could be found with low efficiency in the peripheral blood of healthy donors only following long-term in vitro stimulation with the cognate peptide
To see whether a T-cell-mediated immune response against COA-1 and tumor cell lines could be detected in the peripheral blood of colorectal cancer patients, we collected PBMCs from four patients at early stage of the disease and from seven patients with metastatic tumor and used them for in vitro stimulation with the immunogenic tumor-associated antigen (TAA)-derived epitope COA1441-460
Summary
Experimental Design: Antigen- and tumor-specific immunologic responses of peripheral blood mononuclear cells (PBMC) stimulated in vitro with the MHC class II-associated immunogenic epitope of COA-1 (FSTFPPTLYQDDTLTLQAAG) were analyzed by IFN-g ELISPOTassay. T-cell-mediated responses directed against defined TAAs were commonly detected in the peripheral blood of patients with tumor from different histologic origin (22 – 25) Along this line, an antigen-specific natural T-cell. We evaluated whether this antigen could elicit antitumor-specific T-cell-mediated responses in colorectal cancer patients.We found MHC class II-associated COA-1 and colorectal cancer-reactive CD4+ T cells in the peripheral blood of colorectal cancer patients with advanced stage but not with early disease. Further studies are needed to determine whether even COA-1-deriving epitopes recognized in the context of class I HLA can be associated with the progression of the disease, this study provides a first important evidence of the immunogenicity of thisTAA for both CD4+ and/or CD8+ T cells, suggesting that COA-1can represent an efficient tool to design new vaccination protocols for colorectal cancer patients. More effective immunotherapy treatments need to be defined by implementing the immunologic characterization of tumor patients and by manipulating different effector mechanisms to activate specific T-cell response directed to a broader TAA and epitope repertoire
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
