PD-L1 and VEGF dual blockade enhances anti-tumor effect on brain metastasis in hematogenous metastasis model
Chinami Masuda1, Shinichi Onishi2, Keigo Yorozu2
1Product Research Department, Chugai Pharmaceutical Co., Ltd., Chugai Life Science Park Yokohama, 216, Totsuka-Cho, Totsuka-Ku, Yokohama, Kanagawa, 244-8602, Japan. kojima.chinami41@chugai-pharm.co.jp.
Abstract:
Immunotherapy improves survival outcomes in cancer patients, but there is still an unmet clinical need in the treatment of brain metastases. Here, we used a mouse model to investigate the antitumor effect of programmed death-ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) dual blockade on metastatic brain tumors and evaluated immune responses during treatment. After establishing hematogenous brain metastasis by transplanting murine bladder carcinoma MBT2 cells stably expressing secNLuc reporter via the internal carotid artery of C3H/HeNCrl mice, we observed the formation of metastases not only in the brain parenchyma but also in the ventricles. The observed pathological areas showed that metastases in the ventricle were histologically larger than that in the brain parenchyma. Regarding the total tumor burden in the whole brain as revealed by Nluc activities, the combination of anti-PD-L1 antibody and anti-VEGF antibody showed a stronger anti-tumor effect than each single agent. Anti-PD-L1 antibody alone enhanced CD8+ T cell priming in regional lymph nodes, increased the proportion of activated CD8+ T cells in whole brain, and increased the density of CD8+ cells in the brain parenchyma. Furthermore, anti-VEGF antibody alone decreased microvessel density (MVD) in ventricular metastases, and the combination treatment increased intratumoral CD8+ cell density in the brain parenchyma and ventricular metastases. These results suggest that PD-L1 blockade enhanced cancer immunity not only in brain metastases lesions but also in the regional lymph nodes of the metastases, and that the addition of VEGF blockade increased the antitumor effect by increasing the infiltration of activated CD8+ T cell and decreasing MVD.
Insights
Dual blockade of programmed death-ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) shows potent antitumor effects against brain metastases in mice. This combination therapy enhances anti-tumor immunity and T cell infiltration, offering a promising strategy for treating brain tumors.
Area of Science:
- Immunology
- Oncology
- Neuroscience
Background:
- Immunotherapy has improved cancer patient survival, but brain metastases remain a significant clinical challenge.
- Effective treatment strategies for brain metastases are urgently needed.
Purpose of the Study:
- To investigate the antitumor effects of dual blockade of programmed death-ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) on brain metastases.
- To evaluate the associated immune responses during combination therapy in a preclinical mouse model.
Main Methods:
- Established hematogenous brain metastases using murine bladder carcinoma MBT2 cells in C3H/HeNCrl mice.
- Administered anti-PD-L1 and anti-VEGF antibodies, both as single agents and in combination.
- Assessed tumor burden via Nluc activity and evaluated immune cell populations (CD8+ T cells) and microvessel density (MVD).
Main Results:
- Combination therapy demonstrated a superior antitumor effect compared to single-agent treatments.
- Anti-PD-L1 enhanced CD8+ T cell priming in lymph nodes and increased T cell density in the brain.
- Anti-VEGF reduced MVD, and combination therapy further increased intratumoral CD8+ T cell infiltration.
Conclusions:
- PD-L1 blockade boosts anti-tumor immunity within brain metastases and regional lymph nodes.
- VEGF blockade addition enhances the efficacy of PD-L1 blockade by increasing CD8+ T cell infiltration and reducing MVD.
- Combined PD-L1 and VEGF blockade represents a promising therapeutic approach for brain metastases.
