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.

Prognostic factors in Epstein-Barr virus-associated stage I–III gastric carcinoma: Implications for a unique type of carcinogenesis

“…These extensive intratumoral inflammatory components are composed of activated cytotoxic T, nature killer and mature dendritic cells (9,15,20). The T cell infiltration has been correlated to intratumoral FoxP3-positive regulatory T cells (21). Some authors hypothesized that the intratumoral inflammatory reaction represents an effective host immune reaction against tumor cells (9,20,22).…”

HER2/neu Gene Amplification and Protein Overexpression in Gastric and Gastroesophageal Junction Adenocarcinoma: A Review of Histopathology, Diagnostic Testing, and Clinical Implications

“…Intratumoral homogeneity of HER2 staining may suggest that overexpression occurs as an early event in tumor progression. In addition, Haas et al 28 studied a group of 52 GEJ carcinomas and found no correlation between HER2 overexpression/amplification and tumor stage.…”

Non-Steroidal Anti-Inflammatory Drugs Use Is Associated with Reduced Risk of Inflammation-Associated Cancers: NIH-AARP Study

“…Inflammation has been linked to several cancers, including cancers of the colon, liver, stomach, and gallbladder. Inflammation is involved in cancer initiation, progression, angiogenesis, invasion, and metastasis and can be prompted by several factors, including infection, smoking, alcohol use, and obesity [1] – [4] . Therefore, it is plausible that NSAIDs could attenuate the risks of cancers for which these causes of inflammation are risk factors.…”