HLA-E over-expression in colorectal cancer patients decreases disease free survival

ESTRELLA M. LEVY; MICHELE BIANCHINI; ERIKA M. VON EUW; MARIA M. BARRIO; DAVID FURMAN; ALICIA I. BRAVO; ENZO DOMENICHINI; CARLOS MACAGNO; VICTOR PINSKY; CINZIA ZUCCHINI; LUISA VALVASSORI; JOSÉ MORDOH

Los Angeles

Congreso; American Association for Cancer Research; 2007

HLA-E is a non-classical MHC molecule whose expression by target tumor cells could result in inhibition of the lytic process induced by natural killer (NK) cells. However, HLA-E expression in colorectal cancer (CRC) patients needs to be better characterized; moreover, the clinical significance and prognostic value for its expression in this cancer requests further investigation.To address its potential role in CRC immunobiology, we assessed the expression of HLA-E at the transcript level by qRT-PCR in micro-dissected epithelium samples and, at the protein level by semiquantitative immunohistochemistry on paraffin embedded tissue sections on 42 biopsies of CRC patients, 43% Dukes B, and 57% Dukes C; furthermore, we studied their potential relationship with the CD57+ CD8+ T cells infiltrate. In addition, we first characterized in vitro the regulatory mechanism of HLA-E by IFN-ã, and afterwards the expression of this cytokine was studied at the transcript level by qRT-PCR and at the protein level by IHQ in the epithelium of CRC tumors and normal samples.Our results showed that HLA-E transcript and protein are spontaneously over-expressed in a significant proportion of CRC tumor biopsies, as compared with the normal mucosa. Furthermore, due to the large sample number and strong clinical-pathologic database, we showed that up-regulation of HLA-E could be a marker of shorter disease free survival. We observed that after 66 months of follow-up, 62% of the low HLA-E expression patients were disease free, as compared to only 28% of high HLA-E expression patients. Moreover, IFN-ã up-regulates in vitro the expression of membrane HLA-E independently of protein synthesis, as we demonstrated in five CRC cell lines. This mechanism could have important biological consequences since the tumor could rapidly respond to immune attack. We also demonstrated that IFN-ã mRNA and protein are up-regulated at the tumor microenvironment.The results from our study clearly show that expression of high levels of HLA-E is associated with a poor prognosis, suggesting that this molecule may render tumors less susceptible to immune attack. Although the IFN-ã regulation mechanisms need further investigation, we provide evidence that this cytokine, within the tumor microenvironment, is promoting HLA-E over-expression in the tumor epithelial cells.