Therapeutic effect and mechanism of regulating cellular immune function of chemotherapy combined with PD-1 inhibitor in the first-line treatment of Lewis xenografts

Abstract

Objective To investigate the efficacy of chemotherapy combined with programmed death-1 (PD-1) inhibitor in the first-line treatment of Lewis xenografts and its possible mechanism of regulating cellular immune function. Methods Lewis xenografts mouse model was established. The mice were randomly divided into control, chemotherapy, immunotherapy and combination group according to the method of random number table (10 in each group), and each group separately received saline, cisplatinum, PD-1 inhibitor and cisplatinum combined with PD-1 inhibitor. The tumor growth and survival of each group were observed. Flow cytometry was used to detect and compare the proportion of CD8+ T cells and CD4+ CD25+ FOXP3+ regulatory T cells (Treg cells). Results On the second day after treatment, the tumor volume of Lewis xenografts in control group, chemotherapy group, immunotherapy group and combination group were (1 662.0±209.0) mm3, (1 189.2±155.6) mm3, (991.1±146.6) mm3 and (761.7±141.8) mm3, with statistically significant difference (F=29.78, P<0.001). The tumor volume in the three treatment groups were significantly smaller than that in control group, combination group was significantly smaller than chemotherapy group and immunotherapy group, and immunotherapy group was significantly smaller than chemotherapy group (all P<0.05). Three mice died during the experiment (two in control group and one in chemotherapy group). The median survival time of mice in the four groups were 10, 12, 14 and 18 days, with statistically significant difference (χ2=26.06, P<0.001). The median survival time of mice in the three treatment groups were significantly longer than that in control group, combination group was significantly longer than chemotherapy group and immunotherapy group, and immunotherapy group was significantly longer than chemotherapy group (all P<0.05). The proportions of CD8+ T cells in the peripheral blood of the four groups were (28.5±1.2)%, (33.9±2.9)%, (34.0±2.5)% and (42.4±1.5)%, with statistically significant difference (F=21.32, P<0.001). The proportions of CD8+ T cells in the peripheral blood of the three treatment groups were significantly higher than that of control group, and combination group was significantly higher than chemotherapy group and immunotherapy group (all P<0.05). The proportions of CD8+ T cells in the tumor microenvironment of the four groups were (23.5±1.3)%, (26.7±1.4)%, (34.2±2.8)% and (41.3±2.0)%, with statistically significant difference (F=61.65, P<0.001). The proportions of CD8+ T cells in the tumor microenvironment of the three treatment groups were significantly higher than that of control group, combination group was significantly higher than chemotherapy group and immunotherapy group, and immunotherapy group was significantly higher than chemotherapy group (all P<0.05). The proportions of CD4+ CD25+ FOXP3+ Treg cells in the spleen of the four groups were (8.6±0.5)%, (7.2±0.3)%, (6.3±0.4)% and (5.4±0.4)%, with statistically significant difference (F=37.06, P<0.001). The proportions of CD4+ CD25+ FOXP3+ Treg cells in the spleen of the three treatment groups were significantly lower than that of control group, combination group was significantly lower than chemotherapy group and immunotherapy group, and immunotherapy group was significantly lower than chemotherapy group (all P<0.05). Conclusion Chemotherapy and PD-1 inhibitor can enhance the anti-tumor effect of the body immune system by down-regulating the proportion of Treg cells and up-regulating the proportion of CD8+ T cells, etc. Chemotherapy combined with immunotherapy can improve the anti-tumor immune function, inhibit tumor growth and prolong the survival of mouse with xenograft, which were significantly better than chemotherapy and immunotherapy alone. Key words: Lung neoplasms; Drug therapy; Immunotherapy; T-lymphocyte subsets; PD-1