title: Down-regulation of HLA-A expression correlates with a better prognosis in colorectal cancer patients.
abstract: To evaluate the prognostic impact of human leukocyte antigen class I (HLA-I) expression on immune surveillance in colorectal cancer, we studied 88 curatively resected tumors for HLA-A and HLA-B/C expression and correlated these data to clinical and histopathological parameters. HLA-A was normal (all tumor cells had HLA expression) in 32%, reduced (HLA-negative and -positive tumor cells coexisted) in 56%, or absent (no tumor cells expressed HLA) in 12% of evaluable cases. HLA-B/C was normal in 47%, reduced in 47%, and absent in 7% of the cases. Considering both markers, total HLA-I expression was normal in 27%, reduced in 63%, absent in 7%, and could not be evaluated in 3% of the cases due to absent HLA-A expression in tumor and normal cells. Down-regulation of HLA-A expression significantly correlated with a lower tumor stage (p = 0.005), mucinous tumors (p = 0.05), a lower incidence of recurrences (p = 0.03), and a longer disease-free survival (p = 0.02). Down-regulation of HLA-B/C expression correlated with a lower tumor stage (p < 0.001) and a longer disease-free survival (p = 0.04). In multivariate analysis, HLA-A down-regulation was the only prognostic factor correlated with a longer disease-free survival (p = 0.02). Six tumors were negative for HLA-A and -B/C and did not recur during follow-up. Therefore, we analyzed microsatellite instability (MSI) in these cases. Three of these six tumors indeed showed down-regulation of MLH-1, MSH-2, or MSH-6, indicating a MSI-high phenotype. Beta-2-microglobulin protein expression was lost in five of six of the HLA-I-negative cases, but frame shift mutations in three repetitive sequences in beta2-microglobulin were absent. In contrast, loss of MLH-1, MSH-2, and MSH-6-protein expression was only observed in two of nine matched controls with reduced or normal HLA-A and -B/C expression. Our data showed that HLA-I was down-regulated in 72% of colorectal cancers and provided independent prognostic information for a longer disease-free survival. The better prognosis may be caused by elimination of HLA-negative cells by natural killer cells or by an attenuated tumor aggressiveness, as is seen in tumors with a MSI-high phenotype.
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Anand G
authors.initials: AG
authors.lastname: Menon
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: Rob A E M
authors.initials: RA
authors.lastname: Tollenaar
authors.forename: E
authors.initials: E
authors.lastname: Alphenaar
authors.forename: Marjo
authors.initials: M
authors.lastname: Van Puijenbroek
authors.forename: Hein
authors.initials: H
authors.lastname: Putter
authors.forename: Connie M
authors.initials: CM
authors.lastname: Janssen-Van Rhijn
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: Van De Velde
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Fleuren
authors.forename: Peter J K
authors.initials: PJ
authors.lastname: Kuppen
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D004273:DNA, Neoplasm / Q000032:analysis; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D015234:HLA-A Antigens / Q000096:biosynthesis* / Q000235:genetics; D015235:HLA-B Antigens / Q000096:biosynthesis / Q000235:genetics; D015236:HLA-C Antigens / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens