Anti‑VEGF Antibody Triggers the Effect of Anti‑pd‑l1 Antibody in PD‑L1low and Immune Desert‑like Mouse Tumors.

The efficacy of programmed cell death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) blockade therapy has been demonstrated but is limited in patients with PD-L1(low) or immune desert tumors. This limitation can be overcome by combination therapies that include anti-vascular endothelial growth factor (VEGF) therapy. Such combinations have been investigated in clinical trials for a number of cancer types; however, evidence on the mechanisms underlying their effects in these types of patients is still not sufficient. Therefore, the present study investigated the efficacy and effects on CD8(+) T cell and C-X-C motif chemokine receptor 3 (CXCR3) ligand expression in tumors by combining anti-PD-L1 and anti-VEGF antibodies using an OV2944-HM-1 mouse model with PD-L1(low) and immune desert-like phenotypes. Although the model exhibited anti-PD-L1 insensitivity, anti-PD-L1 antibody treatment combined with anti-VEGF antibody inhibited tumor growth compared with anti-VEGF monotherapy, which itself inhibited tumor growth compared with the control treatment on Day 25. In combination-treated mice, a higher percentage of CD8(+) T cells and higher levels of CXCR3 ligands were observed in tumor tissues compared with those in the anti-VEGF antibody treatment group, which was not significantly different from control treatment on Day 8. The increase in the intratumoral percentage of CD8(+) T cells following the combination treatment was reversed by CXCR3 blocking to the same level as the control. In an anti-PD-L1 insensitive model with PD-L1(low) and immune desert-like phenotypes, although anti-PD-L1 antibody alone was not effective, anti-PD-L1 antibody in combination with anti-VEGF antibody exhibited antitumor combination efficacy with an increase of CD8(+) T cell infiltration, which was suggested to be dependent on the increase of intratumoral CXCR3 ligands. This mechanism could explain the efficacy of anti-PD-L1 antibody and anti-VEGF antibody combination therapy in the clinical setting.