Immune-Depleted Features of HER2-Expressing Gastric Cancer and Immune Remodeling After Trastuzumab-Containing Therapy

Abstract Purpose Immune checkpoint inhibitors (ICIs) have become integral to the treatment of gastric cancer, and pembrolizumab combined with trastuzumab and chemotherapy has improved outcomes in HER2-positive advanced disease. However, the baseline immune phenotype of HER2-expressing gastric cancer and the changes induced by anti-HER2 therapy remain incompletely defined. We investigated the local immune microenvironment associated with HER2 expression and explored immune changes after trastuzumab-containing preoperative therapy. Methods Three complementary analyses were performed. First, HER2 expression, CD8 + T-cell infiltration, and PD-L1 combined positive score (CPS) were assessed by immunohistochemistry in 64 gastrectomy specimens without preoperative therapy. Second, The Cancer Genome Atlas gastric cancer dataset was used to examine ERBB2 amplification in relation to somatic mutation count, cytolytic activity (CYT) score, and CIBERSORT-estimated immune-cell fractions. Third, paired pretreatment biopsy and post-treatment resection specimens from six patients with HER2-positive gastric cancer who received trastuzumab-containing preoperative therapy were analyzed for CD8, PD-L1, PD-L2, SIRPα, and CD80. Results The IHC 2+/3 + group showed significantly lower CD8 + T-cell infiltration and lower PD-L1 CPS than the IHC 0/1 + group (P = 0.04 and P = 0.03, respectively). In TCGA, ERBB2-amplified tumors had lower somatic mutation counts and CYT scores (both P < 0.0001), together with lower estimated fractions of several immune-cell populations, including CD8 + T cells. In the six paired cases, CD8, PD-L1, PD-L2, and SIRPα increased significantly after therapy, whereas CD80 did not significantly change. Conclusion Higher HER2 expression and ERBB2 amplification were associated with an immune-depleted phenotype in gastric cancer. Conversely, trastuzumab-containing therapy was associated with increased CD8 + T-cell infiltration and checkpoint-related molecule expression, suggesting treatment-associated remodeling toward a more inflamed tumor microenvironment. These findings provide a biological framework for combining HER2-directed therapy with PD-1/PD-L1 blockade.