title: High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability.
abstract: Microsatellite instability (MSI) characterizes colorectal carcinomas (CRCs) in hereditary nonpolyposis colorectal cancer (HNPCC) syndrome and a proportion of sporadic CRCs. These MSI+ CRCs share several clinicopathological features, including a reputation for better survival rates than MSI- cases and a pronounced stromal inflammatory reaction of still undefined nature. In the present study, the presence, spatial distribution, and activation status of infiltrating cytotoxic effectors were investigated comparatively in 18 MSI+ and 37 MSI- CRCs by immunohistochemistry. The frequency of apoptosis was also evaluated by morphology and in situ end-labeling. MSI+ cases carried significantly higher numbers of cytotoxic lymphocytes infiltrating within neoplastic epithelial structures, as shown by immunostaining for CD3 (15.1 +/- 6.2 versus 4.6 +/- 4.1, P < 0.001), CD8 (13 +/- 6.4 versus 3.7 +/- 3.8, P < 0.001), and TIA-1 (11.2 +/- 6.5 versus 1.9 +/- 1.7, P < 0.001). These cytotoxic effectors were globally more activated in MSI+ than in MSI- tumors, as revealed by the expression of granzyme B (5.3 +/- 4.5 versus 0.6 +/- 1.3, P < 0.001). In MSI+ CRCs, the number of intraepithelial activated cytotoxic lymphocytes was significantly correlated with the proximal location of the tumor, a poorly differentiated phenotype, and the presence of peritumor lymphoid nodules. Multivariate analysis revealed that MSI was the major determinant of the presence of activated cytotoxic intraepithelial lymphocytes. Moreover, MSI+ CRCs also showed a significantly higher percentage of tumor cells undergoing apoptotic cell death (4.1 +/- 2.1 versus 2.6 +/- 1.1, P < 0.0001, by the TUNEL method), often located in close proximity of activated cytotoxic lymphocytes. These results are consistent with the presence of anti-tumor cytotoxic immune responses in most of MSI+ CRCs, a phenomenon that may at least in part contribute to the survival advantage ascribed to these patients.
authors.affiliation: Divisions of Experimental Oncology, Centro di Riferimento Oncologico, Aviano City Hospital, Belluno, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Dolcetti
authors.forename: A
authors.initials: A
authors.lastname: Viel
authors.forename: C
authors.initials: C
authors.lastname: Doglioni
authors.forename: A
authors.initials: A
authors.lastname: Russo
authors.forename: M
authors.initials: M
authors.lastname: Guidoboni
authors.forename: E
authors.initials: E
authors.lastname: Capozzi
authors.forename: N
authors.initials: N
authors.lastname: Vecchiato
authors.forename: E
authors.initials: E
authors.lastname: Macrì
authors.forename: M
authors.initials: M
authors.lastname: Fornasarig
authors.forename: M
authors.initials: M
authors.lastname: Boiocchi
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D004848:Epithelium / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D020287:In Situ Nick-End Labeling; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD