Histological differentiation impacts the tumor immune microenvironment in gastric carcinoma: Relation to the immune cycle

Abstract

Background: Various histological types of gastric carcinomas (GCs) differ in terms of their pathogenesis and their preexisting background, both of which could impact the tumor immune microenvironment (TIME). However, the current understanding of the immune contexture of GC is far from complete.

Aim: To clarify the tumor-host immune interplay through histopathological features and the tumor immune cycle concept.

Methods: In total, 50 GC cases were examined (15 cases of diffuse GC, 31 patients with intestinal-type GC and 4 cases of mucinous GC). The immunophenotype of GC was assessed and classified as immune desert (ID), immune excluded (IE) or inflamed (Inf) according to CD8+ cell count and spatial pattern. In addition, CD68+ and CD163+ macrophages and programmed death-ligand 1 (PD-L1) expression were estimated.

Results: We found that GCs with different histological differentiation demonstrated distinct immune contexture. Most intestinal-type GCs had inflamed TIMEs rich in both CD8+ cells and macrophages. In contrast, more aggressive diffuse-type GC more often possessed ID characteristics with few CD8+ lymphocytes but abundant CD68+ macrophages, while mucinous GC had an IE-TIME with a prevalence of CD68+ macrophages and CD8+ lymphocytes in the peritumor stroma. PD-L1 expression prevailed mostly in intestinal-type Inf-GC, with numerous CD163+ cells observed. Therefore, GCs of different histological patterns have specific mechanisms of immune escape. While intestinal-type GC was more often related to PD-L1 expression, diffuse and mucinous GCs possessing more aggressive behavior demonstrated low immunogenicity and a lack of tumor antigen recognition or immune cell recruitment into the tumor clusters.

Conclusion: These data help to clarify the links between tumor histogenesis and immunogenicity for a better understanding of GC biology and more tailored patient management.

Keywords: Gastric carcinoma; Tumor associated macrophages; Tumor immune microenvironment; Tumor infiltrating lymphocytes.

Figure 1

Density of immune cells in gastric carcinoma of different histological types. H&E and immunohistochemistry (× 100). Figures demonstrate differences in infiltration of various histological type gastric carcinoma by immune cells, including entire population of T-lymphocytes (CD3), T-cytotoxic cells (CD8), M1 and M2 macrophages (CD68 and CD163 respectively). GC: Gastric carcinoma.

Figure 2

Density and spatial distribution of macrophages in gastric carcinoma of different histological types. Immunohistochemistry for CD68. A and B: Intestinal type gastric carcinoma (GC) of inflamed tumor immune microenvironment (TIME) (A) with high count of CD68+ cells forming dense meshwork (B) inside the tumor. (A: × 100, B: × 200); C: High number of intratumor CD68+ cells of diffuse type GC of ID TIME, × 200; D: Prevalence of CD68+ cells in peritumor stroma of mucinous GC of IE TIME, × 200.

Figure 3

Relationship between programmed death-ligand 1 expression, gastric carcinoma immunophenotype and number of M1 and M2 macrophages. A: Frequency of programmed death-ligand 1 (PD-L1) expression in gastric carcinoma (GC) of different tumor immune microenvironment (TIME); B: PD-L1 expression in tumor cells of Inflamed TIME GC, immunohistochemistry for PD-L1, × 50; C and D: number of M1 (C) and M2 (D)-macrophages in GC regarding PD-L1 expression. PD-L1: Programmed death-ligand 1; CPS: Combined positive score.