Expression of PD1/PDL1 in gastric cancer at different microsatellite status and its correlation with infiltrating immune cells in the tumor microenvironment

Abstract

Objective: The microsatellite status and tumor immune microenvironment have a remarkable influence on tumor immunotherapy. This study was performed to investigate programmed cell death protein 1/programmed death ligand 1 (PD1/PDL1) expression and their correlations with CD8+ T cell/CD68+ macrophage (CD68+ M) densities in gastric cancer (GC) at different microsatellite statuses. Methods: The expression of MLH1, PMS2, MSH2, and MSH6 was detected via immunohistochemistry (IHC) to determine the microsatellite status in 215 GC samples obtained from surgical resections. Furthermore, the expression of PD1, PDL1, CD8, and CD68 was detected in the samples via IHC, and the differences and correlations in GC at different microsatellite statuses were then analyzed. PDL1 expression in tumor cells was labeled as PDL1[T], while expression of PD1 and PDL1 in tumor-infiltrating immune cells was labeled as PD1 and PDL1, respectively. Kaplan-Meier analysis was used to evaluate the significance of PD1/PDL1 expression in determining overall survival. Multivariate Cox regression analysis was performed using SPSS software. P-values were determined using the log-rank test. Results: Our results indicated that PD1, PDL1[T], and PDL1 positivity rates were 59%, 35%, and 57% in 46 microsatellite unstable (MSI) GCs and 45%, 22%, and 40% in 169 microsatellite stable (MSS) GCs, respectively. Compared with MSS GC, PD1, PDL1[T], and PDL1 expression was higher in MSI GC (P = 0.109, 0.090, and 0.044, respectively). Additionally, CD8+ T cell and CD68+ M densities were higher in MSI GC than in MSS GC (P = 0.537 and <0.001, respectively). Additionally, CD8+ T cell/CD68+ M densities were evaluated according to tumor center and invasion front. We found that PD1 expression was significantly correlated with CD8+ T cell density at the invasion front of the MSI GC (P = 0.031), whereas PDL1 expression was significantly correlated to high CD68+ M density in the tumor center and invasion front of MSS GC (P = 0.001 and 0.014, respectively). Survival analysis showed that patients with PD1-positive and PDL1[T]/PDL1-negative GC had better prognosis (P = 0.012, 0.005, and 0.022, respectively). Multivariate Cox survival analysis showed that PDL1[T] was an independent prognostic factor for GC. Conclusion: The results suggested that PD1/PDL1 expression and immune response varied at different microsatellite statuses in GC. PD1/PDL1 expression was correlated with CD8+ T cell/CD68+ M densities in GC at different microsatellite statuses, especially at the invasion front. The patients exhibiting high PD1/PDL1 expression or high CD8+ T cell/CD68+ M densities MSI GC might be potential beneficiaries of PD1/PDL1 immunotherapy.

Case Report: Favorable Response and Manageable Toxicity to the Combination of Camrelizumab, Oxaliplatin, and Oral S-1 in a Patient With Advanced Epstein–Barr Virus-Associated Gastric Cancer

“…Enriched tumor-infiltrating immune cells (lymphocyte and tumor-associated macrophages) exist in the EBVaGC microenvironment (9,10). The density of CD68+macrophages was significantly higher in EBVaGC patients compared to Epstein-Barr virus-negative gastric cancer (EBVnGC), which was positively correlated with the expression rate of PD-L1 (11,12). Compared with EBVnGC, the density of PD-L1+ tumor infiltrating immune cells was significantly greater in EBVaGC (10).…”

An Immunity-Associated lncRNA Signature for Predicting Prognosis in Gastric Adenocarcinoma

“…Two phase III clinical trials have reported that there is a positive correlation between higher PD-L1 expression in gastric cancer tissues and better treatment outcomes, but negative PD-L1 expression is a negative predictor of pembrolizumab survival benefit [ 21 , 48 ]. Wang et al also pointed out that gastric cancer patients with PD1/PD-L1 high expression may be potential beneficiaries of PD1/PD-L1 immunotherapy [ 49 ]. The upregulation of TIM-3 expression in gastric cancer is associated with poor prognosis, tumor lymph node metastasis, and advanced clinical staging of gastric cancer patients [ 50 , 51 ].…”

Amygdalin suppresses the proliferation, migration and EMT of gastric cancer cells by inhibiting TGF-β/Smad signal pathway

“…In the early stage of gastric cancer, there are no obvious symptoms. For advanced gastric cancer, traditional surgical resection and chemoradiotherapy have little effect, and so there is still the need to develop effective treatment drugs [12]. Amygdalin was found to possess huge potentials for the treatment of gastric cancer [13].…”