HLA-E/β2 microglobulin overexpression in colorectal cancer is associated with recruitment of inhibitory immune cells and tumor progression

• Published in: International journal of cancer Vol. 131; no. 4; pp. 855 - 863
• Main Authors: Bossard, Céline, Bézieau, Stéphane, Matysiak-Budnik, Tamara, Volteau, Christelle, Laboisse, Christian L., Jotereau, Francine, Mosnier, Jean-François
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.08.2012; Wiley-Blackwell
• Subjects: Aged; Antigens, CD - immunology; beta 2-Microglobulin - metabolism; Biological and medical sciences; Biomarkers, Tumor - metabolism; colorectal cancer; Colorectal Neoplasms - immunology; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Disease Progression; Female; Gastroenterology. Liver. Pancreas. Abdomen; Histocompatibility Antigens Class I - metabolism; HLA-E; HLA-E Antigens; Humans; Immunohistochemistry; Immunophenotyping; Male; Medical sciences; natural killer cells; Prognosis; prognostic biomarker; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Survival Analysis; Tissue Array Analysis; Tumor Escape; tumor-infiltrating lymphocytes; Tumors; HLA-System; Rectal disease; Prognosis; Colorectal cancer; Biological marker; Gene overexpression; Tumor infiltrating lymphocyte; Malignant tumor; Recruitment; HLA-E; Colonic disease; Natural killer cell; natural killer cells; Cancerology; Digestive diseases; Intestinal disease; prognostic biomarker; tumor-infiltrating lymphocytes; Tumor cell; Cancer; β2-Microglobulin
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.26453

The host immune response plays a major role in colorectal carcinoma (CRC) progression. A mechanism of tumor immune escape might involve expression of the human leucocyte antigen (HLA)‐E/β2m on tumor cells. The inhibitory effect of HLA‐E/β2m on CD8+ cytotoxic T lymphocytes and natural killer (NK) cells is mediated by the main HLA‐E receptor CD94/NKG2A. As the pathophysiological relevance of this mechanism in CRC remains unknown, this prompted us to examine, in situ, in a series of 80 CRC (i) the HLA‐E and β2m coexpression by tumor cells, (ii) the density of CD8+, cytotoxic, CD244+ and NKP46+ intraepithelial tumor‐infiltrating lymphocyte (IEL‐TIL) and (iii) the expression of CD94/NKG2 receptor on IEL‐TIL. These data were then correlated to patient survival. We provided (i) the in situ demonstration of HLA‐E/β2m overexpression by tumor cells in 21% of CRC characterized by an overrepresentation of signet ring cell carcinomas, mucinous carcinomas and medullary carcinomas, (ii) the significant association between HLA‐E/β2m overexpression by tumor cells and increased density of CD8+ cytotoxic, CD244+ and CD94+ IEL‐TIL and (iii) finally, the unfavorable prognosis associated with HLA‐E/β2m overexpression by tumor cells. Our findings show that HLA‐E/β2m overexpression is a surrogate marker of poor prognosis and point to a novel mechanism of tumor immune escape in CRC in restraining inhibitory IEL‐TIL.