Identification and validation of a novel survival prediction model based on the T cell phenotype in tumor immune microenvironment and peripheral blood for the prognosis in gastric cancer

Abstract

Abstract Background The correlation and difference of T cells phenotype between peripheral blood lymphocytes (PBLs) and tumor immune microenvironment (TIME) in patients with gastric cancer (GC) is not clear. We aimed to characterize the phenotypes of CD8+ T cells in tumor infiltrating lymphocytes (TILs) and PBLs in patients with different outcomes and to establish a useful survival prediction model. Methods Multiplex immunofluorescence staining and flow cytometry were used to detect the expression of inhibitory molecule (IM) and active marker (AM) in CD8+TILs and PBLs, respectively. The role of these parameters in 3-year prognosis was assessed by receiver operating characteristic. Then, we divided patients into two TIME clusters (TIME-A/B) and two PBL clusters (PBL-A/B) by unsupervised hierarchical clustering based on the results of multivariate analysis, and used Kaplan-Meier method to analyze the difference in prognosis between each group. Finally, we constructed and compared three survival prediction models based on Cox regression analysis, and further validated the efficiency and accuracy in the internal and external cohort. Results The percentage of PD-1+CD8+TILs, TIM-3+CD8+TILs, PD-L1+CD8+TILs, PD-L1+CD8+PBLs and the density of PD-L1+CD8+TILs were independent risk factors, while the percentage of TIM-3+CD8+PBLs was an independent protective factor. The patients in TIME-B showed a worse 3-year overall survival (OS) (HR: 3.256, 95%CI: 1.318–8.043, P = 0.006), with a higher density of PD-L1+CD8+TILs (P < 0.001) and percentage of PD-1+CD8+TILs (P = 0.017) and PD-L1+CD8+TILs (P < 0.001) compared to TIME-A group. The patients in PBL-B showed a higher positivity of PD-L1+CD8+PBLs (P = 0.042), LAG-3+CD8+PBLs (P < 0.001), TIM-3+CD8+PBLs (P = 0.003), PD-L1+CD4+PBLs (P = 0.001), LAG-3+CD4+PBLs (P < 0.001) and poorer 3-year OS (HR: 0.124, 95%CI: 0.017–0.929, P = 0.015) compared to PBL-A group. In our three survival prediction models, Model 3, which was based on the percentage of TIM-3+CD8+PBLs, PD-L1+CD8+TILs and PD-1+CD8+TILs, showed the best sensitivity (0.950, 0.914), specificity (0.852, 0.857) and accuracy (κ = 0.787, P < 0.001; κ = 0.771, P < 0.001) in the internal and external cohort, respectively. Conclusion We established a comprehensive and robust survival prediction model based on the T cell phenotype in TIME and PBLs for the prognosis in GC.