Strong HLA-DR expression in microsatellite stable carcinomas of the large bowel is associated with good prognosis

Abstract

Progression of colorectal cancer may follow either of two main genetic routes: the chromosome- or microsatellite-instability pathways. Association between the patients' prognosis and microsatellite instability has been questioned. Improved survival has previously been found in patients with expression of HLA-DR antigens on their tumour cells. In this study, the expression of HLA-DR antigen was investigated by immunohistochemistry in 357 large bowel carcinomas stratified by microsatellite instability status. Sixteen per cent of the tumours showed strong HLA-DR expression and 35% had weak DR expression. We confirmed that patients with strong positive HLA-DR staining had improved survival ( P <0.001) compared to patients with no HLA-DR expression. Strong epithelial HLA-DR staining was significantly associated with high level of microsatellite instability ( P <0.001). In the subgroup of tumours with characteristics typical of the chromosomal instability phenotype, i.e. in microsatellite-stable tumours, the patients positive for the HLA-DR determinants showed better survival than those without HLA-DR expression. The protective effect of HLA-DR expression on survival was confirmed by multivariate analysis, both in the whole patient group and in the microsatellite-stable/microsatellite instability-low group. This might be explained by enhanced T-cell mediated anti-tumour immune responses against tumour cells in the HLA-DR positive tumours. The finding of better patient survival in the subgroup of strong HLA-DR positive microsatellite-stable tumours may have clinical implications for these patients. British Journal of Cancer (2002) 87 , 756–762. doi: 10.1038/sj.bjc.6600507 www.bjcancer.com © 2002 Cancer Research UK

Epigenetic inactivation of class II transactivator (CIITA) is associated with the absence of interferon-γ-induced HLA-DR expression in colorectal and gastric cancer cells

“…In that regard, the prognoses of colorectal cancers strongly correlate with the infiltration of CD4 þ lymphocytes, which recognize tumor antigen presented with MHC class II molecules (Andersen et al, 1993;Lovig et al, 2002), so that colorectal cancers that lack HLA-DR have worse prognoses than those that do (Lovig et al, 2002). For these reasons, understanding the molecular mechanisms regulating expression of MHC class II molecules may represent an important step toward developing efficient immunotherapies with which to treat gastrointestinal cancers.…”

“…For unknown reasons, gastrointestinal cancer cells often do not express MHC class II molecules (e.g., HLA-DR), which are associated with T-cell-mediated antitumor immune responses (McDougall et al, 1990;Lovig et al, 2002). In that regard, the prognoses of colorectal cancers strongly correlate with the infiltration of CD4 þ lymphocytes, which recognize tumor antigen presented with MHC class II molecules (Andersen et al, 1993;Lovig et al, 2002), so that colorectal cancers that lack HLA-DR have worse prognoses than those that do (Lovig et al, 2002).…”

“…However, recent evidence suggests that CD4 þ lymphocytes also play an important role in tumor rejection (Toes et al, 1999;Ossendorp et al, 2000). In fact, expression of MHC class II molecules is now known to be associated with a better prognosis in colorectal cancer (Lovig et al, 2002). Expression of MHC class II is induced by interferon (IFN)-g and is tightly regulated at the level of transcription by several RFX family genes (RFX-5, RFX-AP, RFX-B and RFX-ANK) and the transactivator CIITA (Ting and Trowsdale, 2002).…”

HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance

“…[34][35][36][37][38] These different results may reflect differences in the methodology and antibodies used, in the characteristics of the patients' population included in the studies and in the molecular pathogenesis of the disease. In this context, it is noteworthy that HLA class II antigen expression in CRC is closely related to the high-level microsatellite instability (MSI-H) phenotype 33,39 underlining that a precise molecular classification is required to obtain reliable information about the frequency of HLA class II antigen expression in defined tumor subtypes. 37 This conclusion is further supported by the observation in head and neck cancers, where HLA class II antigen expression is related to human papillomavirus infection of the lesions.…”

HLA‐DRB1*13:01 allele in the genetic susceptibility to colorectal carcinoma

“…[3][4][5] Importantly, HLA class II antigen expression in solid tumor cells has been associated with favorable and unfavorable prognosis of CRC patients. [6][7][8][9] The reason(s) why that happens is (are) uncertain. 8 HLA class II antigen polymorphisms have been also implicated in conferring genetic susceptibility to immune-mediated diseases and tumors.…”