Association of tumor-infiltrating T lymphocytes with intestinal-type gastric cancer molecular subtypes and outcome

Abstract

While host immune response is likely to be important for the prognosis of gastric cancer patients, detailed information on the T lymphocyte infiltration in different gastric cancer subtypes is lacking. Here, we studied the presence of CD3, CD8, and FOXP3 (Forkhead box p3) expressing T lymphocytes in a retrospective cohort of 190 intestinal gastric and gastroesophageal adenocarcinomas. The cancers represented four distinct molecular subtypes: Epstein-Barr virus-positive (EBV+), mismatch-repair-deficient (MMR-D), aberrant TP53, and the "other" subtype. The absolute numbers of CD3+, CD8+, and FOXP3+ T lymphocytes were analyzed in relation with these molecular subtypes and selected clinicopathological parameters. Overall, there was a large variation in the amount of infiltrating T lymphocyte in all molecular subtypes. Among the subtypes, EBV+ cancers differed from the other subtypes in increased lymphocyte infiltration and high CD8+/FOXP3+ ratio. While the TP53 aberrant subtype did not differ in the absolute amount of T lymphocyte, the ratio of CD8+/FOXP3+ and CD3+/FOXP3+ cells was highest in this subtype, possibly reflecting immunosuppression associated with genomic instability. Increased CD3+ and CD8+ T lymphocyte infiltrates were associated with better survival, and remained as independent prognostic factors in a multivariate analysis. This study is the first to investigate lymphocytic infiltration within four molecular subtypes of intestinal-type gastric cancer in a European cohort. The results provide an important addition to the current knowledge of T lymphocyte-dependent immune response in gastric cancer and its prognostic significance.

Keywords: Gastric cancer; Molecular subtypes; Overall survival; Tumor infiltration.

Fig. 1

CD3, CD8, and FOXP3 T lymphocytes in four molecular subtypes of intestinal-type gastric adenocarcinoma. a Representative immunohistochemistry images of the different T lymphocyte subsets and corresponding hematoxylin-eosin images of gastric cancer tumor tissue (from left to right): CD3+ T lymphocytes, CD8+ cytotoxic T lymphocytes, and FOXP3+ regulatory T lymphocytes. Scale bar = 100 μm. b–f Box plot visualization of T lymphocyte subsets in the different intestinal-type gastric cancer molecular subtypes. b CD3+ T lymphocytes. c. CD8+ T lymphocytes. d FOXP3+ T lymphocytes. e CD3+/FOXP3+ lymphocytes. f CD8+/FOXP3+ lymphocytes. Y-axis = number of lymphocytes/0.2mm². Outliers are denoted with a circle.*p = 0.002, **p = 0.001, ***p < 0.0001

Fig. 2

Kaplan-Meier analysis for recurrence-free survival and overall survival of patients with intestinal-type gastric cancer in relation to T lymphocyte infiltration. a Recurrence-free survival (CD3). b and c Overall survival (CD3 and CD8, respectively)