| ObjectiveTo examine the expression of OX40 (CD134, TNFRSF4), OX40 ligand (OX40L, CD252, TNFSF4), Cytotoxic T lymphocyte-associated Antigen-4 (CTLA-4, CD 152) in chronic non-atrophic gastritis, gastric primary benign and malignant tumors and gastric precancerous lesions and the infiltration of their positive lymphocytes, further study their relationship with clinicopathological features of different lesions including their histological sources, with adenoma or not, with intestinal metaplasia or not, pathological differentiation and the T stage, volume, location of gastric cancer and explore the relationship among the expression of OX40, OX40L, CTLA-4 and their influence on the local immunoenvironment of gastric tumors.MethodsThe gastric endoscopic submucosal dissection (ESD) paraffin specimens of 70 patients were collected from Aug 2006 to Feb 2009 in the Department of Endoscopy, Zhongshan Hospital, including chronic non-atrophic gastritis, gastric dysplasia, cancer, stromal tumor, leiomyoma. They were divided into five groups, including 16 cases with chronic non-atrophic gastritis,13 cases with gastric mild-moderate dysplasia,14 cases with gastric severe dysplasia or cancer,14 cases with gastric stromal tumor,13 cases with gastric leiomyoma. For analysis by immunohistochemistry (IHC), 4-micron sections were cut and HE staining was performed to confirm the diagnosis. Then IHC EnVision method was applied to examine the expression of OX40, OX40L, CTLA-4 in tissues with different pathological types and the infiltration of their positive lymphocytes and evaluate their relationship with clinicopathological features of different lesions including their histological sources, with adenoma or not, with intestinal metaplasia or not, pathological differentiation and the T stage, volume, location of gastric cancer.Results1. The level of OX40 expression in parenchymal cells in gastric stromal tumor tissues were higher than that in chronic non-atrophic gastritis, gastric mild-moderate dysplasia, severe dysplasia or cancer, leiomyoma tissues (P<0.05), with that in gastric severe dysplasia or cancer tissues higher than that in gastric leiomyoma tissues (P<0.05), while there were no significant differences in other comparisons among the groups (P>0.05). The level of OX40L expression in parenchymal cells in gastric mild-moderate dysplasia, severe dysplasia or cancer tissues were higher than that in chronic non-atrophic gastritis tissues (P<0.05), with that in gastric mild-moderate dysplasia, severe dysplasia or cancer, stromal tumor tissues higher than that in gastric leiomyoma tissues (P<0.05), while no significant differences were found in other comparisons among the groups (P>0.05). CTLA-4 was expressed in the membrane and cytoplasm of parenchymal cells in gastric mucosal and stromal tumor tissues. The level of its expression in parenchymal cells in gastric severe dysplasia or cancer tissues were higher than that in chronic non-atrophic gastritis and gastric stromal tumor tissues (P<0.05), while no significant differences were found in other comparisons among the groups (P>0.05). CTLA-4 was mostly found in the nuclear of leiomyoma cells, with its positive expression 91.5%.2. Among OX40, OX40L, CTLA-4, there were no significant correlations between their expression and the degree of dysplasia of gastric mild-moderate dysplasia, as well as with adenoma or not, with intestinal metaplasia or not (P>0.05), and they was either not correlated to gastric canceration in the group of gastric severe dysplasia or cancer (P>0.05), to the pathological differentiation, T stage, volume and location of gastric cancer (P>0.05), to the histological sources and pathological differentiation of gastric stromal tumor (P>0.05), to the histological sources of gastric leiomyoma (P>0.05), except that the level of OX40 expression in parenchymal cells in gastric severe dysplasia tissues was higher than that in chronic non-atrophic gastritis, gastric mild-moderate dysplasia and cancer tissues (P<0.05).3. The level of OX40, OX40L, CTLA-4 positive lymphocytes in gastric leiomyoma tissues were lower than that in tissues of other groups (P<0.05).4. Among OX40, OX40L, CTLA-4, there were no significant correlations between the infiltration of their positive lymphocytes and the degree of dysplasia of gastric mild-moderate dysplasia, as well as with adenoma or not,with intestinal metaplasia or not (P>0.05), and they was either not correlated to gastric canceration in the group of gastric severe dysplasia or cancer (P>0.05), to the pathological differentiation, T stage, volume and location of gastric cancer (P>0.05), to the histological sources and pathological differentiation of gastric stromal tumor (P>0.05), to the histological sources of gastric leiomyoma (P>0.05), except that significant correlation was found between the level of OX40 positive lymphocytes and the pathological differentiation of gastric cancer (P<0.05).5. In gastric benign and malignant lesions, there were no significant correlations among the expression of OX40, OX40L, CTLA-4 in parenchymal cells (P>0.05), while positive correlation was found between the level of OX40 positive lymphocytes and that of OX40L positive lymphocytes (P<0.05).Conclusions1. In the gastric mucosal lesions, OX40 expression in the parenchymal cells in gastric severe dysplasia tissues increased; OX40L expression in the parenchymal cells in gastric dysplasia or cancer tissues increased; the level of OX40 positive lymphocytes in the poorly differentiated gastric cancer tissues were higher than that in moderately or highly differentiated ones. All shows that there are anti-dysplasia and anti-tumor immune responses in human body.2. The level of OX40 expression in the parenchymal cells in gastric cancer tissues was lower than that in gastric severe dysplasia tissues, which may not fully activate the local immune response, then was involved in the occurrence and development of gastric cancer.3. The level of CTLA-4 expression in the parenchymal cells in gastric severe dysplasia or cancer tissues was higher than that in chronic non-atrophic gastritis tissues, which inhibit the local immune response, then may be involved in the occurrence and development of gastric cancer.4. In gastric benign and malignant lesions, there was positive correlation between the level of OX40 positive lymphocytes and that of OX40L positive lymphocytes and their interactions may be involved in anti-dysplasia and anti-tumor immune responses in human body.
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