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Overcoming adaptive resistance to anti-VEGF therapy by targeting CD5L.

ABSTRACT: Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) pathway is a powerful tool to combat tumor growth and progression; however, drug resistance frequently emerges. We identify CD5L (CD5 antigen-like precursor) as an important gene upregulated in response to antiangiogenic therapy leading to the emergence of adaptive resistance. By using both an RNA-aptamer and a monoclonal antibody targeting CD5L, we are able to abate the pro-angiogenic effects of CD5L overexpression in both in vitro and in vivo settings. In addition, we find that increased expression of vascular CD5L in cancer patients is associated with bevacizumab resistance and worse overall survival. These findings implicate CD5L as an important factor in adaptive resistance to antiangiogenic therapy and suggest that modalities to target CD5L have potentially important clinical utility.

SUBMITTER: LaFargue CJ

PROVIDER: S-EPMC10133315 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Overcoming adaptive resistance to anti-VEGF therapy by targeting CD5L.

LaFargue Christopher J CJ Amero Paola P Noh Kyunghee K Mangala Lingegowda S LS Wen Yunfei Y Bayraktar Emine E Umamaheswaran Sujanitha S Stur Elaine E Dasari Santosh K SK Ivan Cristina C Pradeep Sunila S Yoo Wonbeak W Lu Chunhua C Jennings Nicholas B NB Vathipadiekal Vinod V Hu Wei W Chelariu-Raicu Anca A Ku Zhiqiang Z Deng Hui H Xiong Wei W Choi Hyun-Jin HJ Hu Min M Kiyama Takae T Mao Chai-An CA Ali-Fehmi Rouba R Birrer Michael J MJ Liu Jinsong J Zhang Ningyan N Lopez-Berestein Gabriel G de Franciscis Vittorio V An Zhiqiang Z Sood Anil K AK

Nature communications 20230426 1

Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) pathway is a powerful tool to combat tumor growth and progression; however, drug resistance frequently emerges. We identify CD5L (CD5 antigen-like precursor) as an important gene upregulated in response to antiangiogenic therapy leading to the emergence of adaptive resistance. By using both an RNA-aptamer and a monoclonal antibody targeting CD5L, we are able to abate the pro-angiogenic effects of CD5L overexpression ...[more]

PMID: 37100807

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Project description:PurposeTumor-associated macrophages (TAMs) are known to contribute to adaptive resistance to anti-vascular endothelial growth factor (VEGF) antibody (AVA) therapy in ovarian cancer. BET (bromodomain and extra-terminal domain) inhibitors (BETi) may have unique roles in targeting TAMs. Our objective was to examine the effects of BETi on TAMs, especially in the context of enhancing the efficacy of AVA therapy.MethodsWe conducted a series of in vitro (MTT assay, apoptosis, flow cytometry, and RNA sequencing) and in vivo (xenograft ovarian cancer model) experiments to determine the biological effects of BETi combined with AVA in ovarian cancer. For statistical analysis, a two-tailed Student's t test (equal variance) or ANOVA was used for multiple groups' comparison, and p < 0.05 was considered significant.ResultsBETi resulted in a dose-dependent decrease in cell viability and induced apoptosis (p < 0.01) in ovarian cancer cells (SKOV3ip1, OVCAR5, and OVCAR8). Treatment with BETi significantly increased apoptosis in THP-1 monocytes and macrophages (PMA-differentiated THP-1; p < 0.01). Furthermore, BETi selectively induced greater apoptosis in M2-like macrophages (PMA and IL-4, IL-13-differentiated THP-1) (31.3%-36.1%) than in M1-like macrophages (PMA and LPS-differentiated THP-1) (12.4%-18.5%) (p < 0.01). Flow cytometry revealed that the percentage of M1-like macrophages (CD68+/CD80+) was significantly increased after treatment with low-dose BETi (ABBV-075 0.1 µM; p < 0.05), whereas the percentage of CD68+/CCR2+ macrophages was significantly decreased (p < 0.001); these findings suggest that BETi may selectively inhibit the survival of CCR2+ macrophages and re-polarize the macrophages into an M1-like phenotype. RNA-seq analysis revealed that BETi selectively targeted macrophage infiltration-related cytokines/chemokines in ovarian cancer (adjusted p < 0.05 and Log2 fold change ≥ 1.5). Finally, using in vivo ovarian cancer models, compared with control or monotherapy, the combination of BETi (ABBV-075) and bevacizumab resulted in greater inhibition of tumor growth and macrophage infiltration (p < 0.05) and longer survival of tumor-bearing mice (p < 0.001).ConclusionsOur findings indicate a previously unrecognized role for BETi in selectively targeting CCR2+ TAMs and enhancing the efficacy of AVA therapy in ovarian cancer.

Dataset Information

Overcoming adaptive resistance to anti-VEGF therapy by targeting CD5L.

Publications

Overcoming adaptive resistance to anti-VEGF therapy by targeting CD5L.

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