High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability
High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability
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DOI：
10.1016/s0002-9440(10)65436-3
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发表时间：
1999-06-01
影响因子：
6
通讯作者：
Boiocchi, M
中科院分区：
文献类型：
--
作者：
Dolcetti, R;Viel, A;Boiocchi, M
微卫星不稳定性(MSI)是遗传性非息肉病性结直肠癌(HNPCC)综合征中结直肠癌(CRC)和部分散发性结直肠癌的特征。这些MSI+CRC有几个共同的临床病理特征，包括存活率比MSI-病例高的名声，以及仍未明确性质的明显间质炎症反应。本研究采用免疫组织化学方法对18例MSI+和37例MSI-CRC中细胞毒效应细胞的存在、空间分布和激活状态进行了对比研究，并通过形态学和原位末端标记法评价了细胞凋亡的发生率。CD3(15.1+/-6.2vs4.6+/-4.1，P<0.001)、CD8(13+/-6.4vs3.7+/-3.8，P<；0.001)和TIA-1(11.2+/-6.5vs1.9+/-1.7P<；0.001)的表达明显增加。颗粒酶B的表达显示，这些细胞毒效应在微粒酶阳性的肿瘤中比微粒酶B的肿瘤中被激活得更多(5.3vs0.61.3P<；0.001)。在MSI+CRC中，上皮内激活的细胞毒性淋巴细胞的数量与肿瘤的近端位置、低分化表型和瘤周淋巴结节的存在显著相关，多因素分析显示MSI是激活的细胞毒性上皮内淋巴细胞存在的主要决定因素。此外，MSI+CRC还显示出显著更高的肿瘤细胞凋亡率(TUNEL法4.1+/-2.1比2.6+/-1.1，P<；0.0001)，通常位于激活的细胞毒性淋巴细胞附近，这些结果与大多数MSI+CRC中存在抗肿瘤细胞毒性免疫反应一致，这一现象可能至少部分地有助于这些患者的生存优势。
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 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 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 effecters 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.