High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability

Microsatellite instability (MSI) characterizes colorectal carcinomas (CRCs) in hereditary nonpolyposis colorectal cancer (HNPCC) syndrome and a propor tion of sporadic CRCs. These MSI+ CRCs share several clinicopathological fe atures, including a reputation for better survival rates than MSI- cases an d a pronounced stromal inflammatory reaction of still undefined nature. In the present study, the presence, spatial distribution, and activation statu s of infiltrating cytotoxic effecters 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 carri ed significantly higher numbers of cytotoxic lymphocytes infiltrating withi n 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). Thes e cytotoxic effecters were globally more activated in MSI+ than in MSI- tum ors, 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 cy totoxic lymphocytes was significantly correlated with the proximal location of the tumor, a poorly differentiated phenotype, and the presence of perit umor lymphoid nodules, Multivariate analysis revealed that MSI was the majo r determinant of the presence of activated cytotoxic intraepithelial lympho cytes. 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 act ivated cytotoxic lymphocytes, These results are consistent with the presenc e of anti-tumor cytotoxic immune responses in most of MSI+ CRCs, a phenomen on that may at least in part contribute to the survival advantage ascribed to these patients.