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Induction of Both CD8⁺ and CD4⁺ T-Cell–Mediated Responses in Colorectal Cancer Patients by Colon Antigen-1

Authors' Affiliations: ¹ Department of Cell Biology and Neurosciences, Istituto Superiore di Sanitá; ² Department of Oncology, A.Fa.R., Ospedale San Giovanni Calibita, Fatebenefratelli; ³ Department of Transfusion Medicine, Azienda Universitaria Policlinico Umberto I, Rome, Italy and ⁴ Unit of Immuno-biotherapy of Melanoma and Solid Tumors, Department of Oncology, San Raffaele Foundation Scientific Institute; ⁵ Unit of Immunotherapy of Human Tumors, Fondazione Istituto Nazionale Tumori; and ⁶ Unit of Transfusion Medicine, Fondazione Instituto Nazionale Tumori, Milan, Italy

Requests for reprints: Cristina Maccalli, Unit of Immuno-biotherapy of Melanoma and Solid Tumors, Department of Oncology, San Raffaele Foundation Scientific Institute, DIBIT, Via Olgettina 58, 20132 Milan, Italy. Phone: 39-2-2643-6118; Fax: 39-2-2643-5602; E-mail: maccalli.cristina{at}hsr.it.

Purpose: 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.

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- ELISPOT assay.

Results: COA-1-specific and tumor-reactive T lymphocytes were isolated from all (n = 7) HLA-DRβ1*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.

Conclusions: 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.

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