PD-1 inhibitor combined with apatinib modulate the tumor microenvironment and potentiate anti-tumor effect in mice bearing gastric cancer

Abstract

Objective: To explore the effect of programmed death 1 (PD-1) inhibitor combined with apatinib on immune regulation and efficacy of the combined therapy in mice bearing gastric cancer (MBGC), and to provide a research basis for enhancing the benefit of immunotherapy in advanced gastric cancer (AGC).

Methods: MBGC were divided into normal saline group (group NS), apatinib group (group A), PD-1 inhibitors group (group B) and PD-1 inhibitors combined with apatinib group (group C). Tumor inhibition rates were calculated. Cytokine levels and expression of immune cells and molecules were detected, and the pathological manifestations of tumor tissues were observed.

Results: Group C had the smallest tumor volume (115.17 ± 16.08 mm³) with a tumor inhibition rate of 89.4% ± 0.69%, significantly increased levels of CD4⁺T and CD8⁺T cells in tumor tissues (P < 0.01), the down-regulated proportion of myeloid-derived suppressor cells (MDSCs) (P < 0.01), and levels of PD-1 of CD8⁺T cells (PD-1⁺CD8⁺T) (P < 0.01). There was no difference in the levels of PD-1⁺CD8⁺T, CD4⁺T cells, and MDSCs between groups B and C. Besides, combination therapy increased the levels of interleukin-2 (IL-2), interferon-gamma (IFN-γ), and tumor necrosis factor-ɑ (TNF-ɑ) in tumor tissue and serum. We also found that the anti-angiogenic effect of apatinib increased programmed death ligand-1 (PD-L1) levels, down-regulated vascular endothelial growth factor receptor 2 (VEGFR-2) levels, and induced an increase in the extent of tumor tissue necrosis.

Conclusion: PD-1 inhibitors in combination with apatinib may help improve treatment outcomes and increase survival benefits in patients with AGC.

Keywords: Apatinib; Combined; Gastric cancer; PD-1; Tumor microenvironment.