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

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.