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

R Dolcetti, A Viel, C Doglioni, A Russo… - The American journal of …, 1999 - Elsevier
R Dolcetti, A Viel, C Doglioni, A Russo, M Guidoboni, E Capozzi, N Vecchiato, E Macrì…
The American journal of pathology, 1999Elsevier
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 …
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 versus1.9 ± 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.
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