Infiltrating and peripheral immune cell analysis in advanced gastric cancer according to the Lauren classification and its prognostic significance

Abstract

Background The correlation between immune cells and the Lauren classification subtypes and their prognostic impact in advanced gastric cancer (AGC) are unknown. Methods Circulating natural killer (NK) cells, CD4 + and CD8 + T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were quantified in peripheral blood mononuclear cells (PBMCs) from 67 patients with untreated AGC enrolled in the PRODIGE 17-ACCORD 20 trial. CD56 + cells (NK), CD8 + , and FoxP3 + (Treg) tumor-infiltrating lymphocytes (TILs) were assessed in tumor samples. Results Circulating NK and Treg proportions were significantly lower in patients with diffuse/mixed-type AGC (n = 27) than those with intestinal type (n = 40; median 6.3% vs 11.5%; p = 0.02 and median 3.3% vs 5.2%; p = 0.03, respectively). Proportions of circulating MDSC, CD4 + and CD8 + T cells were not associated with one pathological type. Among tumorinfiltrating cells, CD8 + T cells, but not NK or FoxP3 + cells, were significantly lower in diffuse/mixed-type AGC (median 21 vs 59 cells/field; p = 0.009). Patients with high circulating NK cell counts (> 17%) had a better overall survival than those with < 17% (HR 0.40; 95% CI [0.15-1.06]; p = 0.04). Patients with high CD8 + TIL counts (> 31 cells/field) had significantly longer overall survival (HR 0.44; 95% CI [0.21-0.92]; p = 0.02). The prognostic value of CD8 + TILs was maintained after adjustment for confounding factors, including the Lauren classification (HR = 0.42; 95% CI [0.18-0.96]; p = 0.039). Conclusion Diffuse/mixed-type AGC has lower rates of CD8 + TILs and circulating NK cells and Tregs than the intestinal type. This "cold tumor" phenotype may be associated with a worse outcome.

Prognostic and Predictive Value of Microsatellite Instability, Inflammatory Reaction and PD-L1 in Gastric Cancer Patients Treated with Either Adjuvant 5-FU/LV or Sequential FOLFIRI Followed by Cisplatin and Docetaxel: A Translational Analysis from the ITACA-S Trial

“…The hypothesis generating from these results could prompt the identification of a subset of GCs, mainly intestinal-type ones, in which the induction of T cell exhaustion is promoted by tumor upregulation of immune-inhibitory checkpoints such as PD-L1. Notably, the "cold tumor" phenotype of diffuse-type cancers has been recently confirmed by using circulating immune biomarkers and may be responsible for the relatively worse outcomes compared with intestinal-type subgroup [23]. In agreement with literature data, MSI status was significantly associated with specific clinicopathological features (i.e., older age, ECOG PS, and intestinal histotype) and with stromal PD-L1 expression but not with inflammatory reaction or tumor PD-L1 expression.…”

Tumor immune response and immunotherapy in gastric cancer

“…Furthermore, previous studies consistently demonstrated that higher TIL densities, such as CD3-or CD8-positive cytotoxic T cells, were associated with better outcome in patients with GC [27,28]. These studies investigated TIL density by immunohisto-chemistry (IHC) of CD3, CD4, CD8, and other markers (Table 1) [29][30][31][32][33][34][35][36][37][38][39][40][41][42]. An image analyzing software was used to quantify TIL density and ensure constant analysis, or TIL density was counted manually.…”

Identification of novel alternative splicing events associated with tumorigenesis, protein modification, and immune microenvironment in early-onset gastric cancer

“…The distribution of tumor-infiltrating lymphocytes in gastric cancer was correlated with the tumor histological type and clinical outcome [44]. On the basis of the immune infiltration data, the immunoscore, a prognostic signature, was established for prognostic predictions of gastric cancer [45,46].…”