Inflammation in gastric adenocarcinoma of the cardia: how do EBV infection, Her2 amplification and cancer progression influence tumor-infiltrating lymphocytes?

Abstract

Tumor-infiltrating lymphocytes (TILs) in gastric adenocarcinoma show a strong compartmentalization with high numbers of lymphocytes in the stroma and low intraepithelial lymphocyte counts. Our previous study has shown stromal regulatory T cells (Treg) to be associated with a beneficial outcome in intestinal type cancer of the cardia. We undertook the present study to further evaluate the immunogenic and inflammatory environment in intestinal-type gastric adenocarcinoma of the cardia. We assessed CXCR3 expression, Epstein-Barr virus (EBV) status, Her2/ERBB2 status and overexpression/amplification using tissue microarrays (immunohistochemistry and in situ hybridization) of 52 patients. The data were correlated to different TIL subset counts (CD3, CD8, GranzymeB, FoxP3 and CD20) and to infiltrating histiocytes (CD68) both in the tumor and the surrounding stromal tissue that were reported earlier. Her2/ERBB2 overexpression/amplification showed no correlation to tumor stage. Moreover, for the first time, we show here that Her2/ERBB2 overexpression/amplification has no correlation to overall or subset-specific TIL infiltration. EBV infection was seen in four cases and showed a strong association with intratumoral CD8(+) T cell infiltration as well as a moderate correlation to stromal CD8(+) T cell accumulation. Intratumoral CD8(+) T cell infiltration was significantly correlated to intratumoral FoxP3(+) Treg infiltration, and to a lesser extent, to stromal FoxP3(+) Treg counts. Stromal CXCR3(+) T cell infiltration showed an inverse correlation to T category. This highlights the importance of stromal immune processes for cancer growth and suggests a subversion of Th1 immunoresponse in cancer progression and underlines the important role of inflammation for early carcinogenesis.