Anti‑VEGF antibody triggers the effect of anti‑PD‑L1 antibody in PD‑L1<sup>low</sup> and immune desert‑like mouse tumors

Ishikura,Nobuyuki; Sugimoto,Masamichi; Yorozu,Keigo; Kurasawa,Mitsue; Kondoh,Osamu

doi:10.3892/or.2021.8247

Anti‑VEGF antibody triggers the effect of anti‑PD‑L1 antibody in PD‑L1^low and immune desert‑like mouse tumors

Authors:
- Nobuyuki Ishikura
- Masamichi Sugimoto
- Keigo Yorozu
- Mitsue Kurasawa
- Osamu Kondoh
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Affiliations: Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa 247‑8530, Japan
Published online on: December 23, 2021 https://doi.org/10.3892/or.2021.8247
Article Number: 36
Copyright : © Ishikura et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

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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‑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.

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