THE IMMUNE MICROENVIRONMENT IMPACTS SURVIVAL IN WESTERN PATIENTS WITH GASTRIC ADENOCARCINOMA
Abhineet Uppal*1, Ahmed Dehal1, Shu-Ching Chang2, Danny Barak3, John R. Jalas1, Anton J. Bilchik1
1Surgical Oncology, John Wayne Cancer Institute, Santa Monica, CA; 2Providence Portland Medical Center, Portland, OR; 3Medstar Georgetown University Hospital, Washington, DC
Background: Expression of CD3+ T cells, CD8+ cytotoxic T cells, CD45RO+ memory T cells and FOXP3+ regulatory T cells at the invasive margin (IM) and tumor center (TC) have correlated with recurrence and survival in gastric adenocarcinoma (GA) patients from East Asia, independent of TNM staging. The reasons for improved survival in East Asians compared with Western patients is a subject of much debate. In this study, we examined whether the immune microenvironment impacts survival in a cohort of Western patients with GA.
Methods: Immunohistochemistry (IHC) of CD3, CD4, CD8, CD45RO and FOXP3 were performed on a randomly selected group of resected GA specimens from 61 Western patients. Standardized image processing with ImageJ was used to quantify the density of staining for each immune cell marker at the IM and TC for each specimen. Correlation between immune cell marker density and stage was performed using a two-way ANOVA. Cutoffs for high or low expression of each marker was determined with maximally selected rank statistics, and multivariate Cox proportional-hazards models constructed to evaluate the relationship between overall survival (OS) and expression of each marker at the IM and TC.
Results: Immune cell density was independent of anatomic staging for all cell populations. Combined expression of CD3 at the TC and IM, CD8 at the IM and CD45RO at the TC was associated with improved OS (HR 0.23, 95% CI:0.06-0.84, p=0.025). A two-fold increase in the ratio of IM CD8 to CD3 was associated with better OS independent of age, stage and systemic therapy (HR 0.19, 95% CI: 0.07-0.51, p=0.001). An increased ratio of TC CD45RO to CD3 was also associated with better survival (HR 0.26, 95% CI: 0.10-0.69, p=0.006). Conversely, the ratio of IM FOXP3 to CD3 was associated with worse survival (HR 4.04, 95% CI 1.49-11.0, p=0.01).
Conclusion: This is the first report in Western patients to demonstrate that increased density of CD3+, CD8+, CD45RO+ and FOXP3+ lymphocytes in GA are associated with OS, independent of age and anatomic stage. Further evaluation of immune-modulating mechanisms may explain survival differences between Western and Eastern patients and provide opportunity for novel treatments.
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