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

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 tumor-infiltrating 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.