Abstract
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-L1low 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-L1low 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-L1low 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.
Highlights
Programmed cell death‐ligand 1 (PD‐L1) is an immune check‐ point molecule expressed on tumor cells and tumor‐infiltrating immune cells, which is involved in the suppression of cancer immunity [1]
Anti‐PD‐L1 antibody combined with anti‐Vascular endothelial growth factor (VEGF) antibody improves tumor control compared with anti‐VEGF antibody alone in an anti‐PD‐L1 insensitive HM‐1 tumor model
In the HM‐1 model, the anti‐VEGF antibody alone significantly inhibited tumor growth compared with the control; the anti‐PD‐L1 antibody alone did not significantly inhibit the tumor growth compared with the control (Fig. 2B)
Summary
Programmed cell death‐ligand 1 (PD‐L1) is an immune check‐ point molecule expressed on tumor cells and tumor‐infiltrating immune cells, which is involved in the suppression of cancer immunity [1]. Anti‐PD‐L1 antibody relieves T cell suppres‐ sion by inhibiting the binding of PD‐L1 to programmed cell death protein 1 (PD‐1) and B7.1 ( known as CD80), which are receptors on effector T cells, and exerts antitumor effects in various types of cancer [2]. Vascular endothelial growth factor (VEGF) has been reported to exert tumor angiogenesis‐inducing activity, and immunosuppressive activity which can attenuate the antitumor immunity elicited by anti‐PD‐L1/PD‐1 therapy through inhibition of dendritic cell (DC) maturation [9,10,11,12] and accumulation of myeloid‐derived suppressor cells (MDSCs) [13]. It has been reported that VEGF blockade may promote antitumor immunity by inhibiting the accumulation of regulatory T‐cells (Tregs) [14]
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