Pericytes augment glioblastoma cell resistance to temozolomide through CCL5-CCR5 paracrine signaling
https://www.nature.com/articles/s41422-021-00528-3
Excessive outgrowth of pericytes in GBM governs the ecology of the perivascular niche, but their function in mediating chemoresistance has not been fully explored.
"Herein, we uncovered that pericytes potentiate DNA damage repair (DDR) in GBM cells residing in the perivascular niche, which induces temozolomide (TMZ) chemoresistance.
We found that increased pericyte proportion correlates with accelerated tumor recurrence and worse prognosis.
Genetic depletion of pericytes in GBM xenografts enhances TMZ-induced cytotoxicity and prolongs survival of tumor-bearing mice.
Mechanistically, C-C motif chemokine ligand 5 (CCL5) secreted by pericytes activates C-C motif chemokine receptor 5 (CCR5) on GBM cells to enable DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-mediated DDR upon TMZ treatment".
Disrupting CCL5-CCR5 paracrine signaling through the brain-penetrable CCR5 antagonist xxmaravirocxx (MVC) potently inhibits pericyte-promoted DDR and effectively improves the chemotherapeutic efficacy of TMZ. GBM patient-derived xenografts with high CCL5 expression benefit from combined treatment with TMZ and MVC.
Our study reveals the role of pericytes as an extrinsic stimulator potentiating DDR signaling in GBM cells and suggests that targeting CCL5-CCR5 signaling could be an effective therapeutic strategy to improve chemotherapeutic efficacy against GBM"
or the AI version
"Preclinical research indicates that
leronlimab (PRO 140), a humanized monoclonal antibody that acts as a C-C motif chemokine receptor 5 (CCR5) antagonist, enhances the cytotoxic effects of temozolomide (TMZ), particularly in cancer types where CCR5 signaling contributes to tumor progression and chemoresistance.
Key Findings on Leronlimab and Temozolomide Interaction:
Mechanism of Action: Leronlimab acts as a CCR5 antagonist, blocking the interaction between CCL5 (a chemokine) and its receptor CCR5, which is often exploited by tumor cells to survive DNA-damaging chemotherapy.
Overcoming Resistance: By targeting the CCL5-CCR5 axis, leronlimab is believed to inhibit pericyte-promoted DNA damage repair (DDR) in tumor cells, thereby mitigating resistance to TMZ.
Enhanced Cell Death: Studies have shown that blocking this pathway increases cell death induced by DNA-damaging chemotherapies like TMZ.
Preclinical Progress: As of March 2025, a preclinical study at the Albert Einstein College of Medicine is underway to analyze the sequencing of temozolomide and leronlimab
https://www.nature.com/articles/s41422-021-00528-3
Excessive outgrowth of pericytes in GBM governs the ecology of the perivascular niche, but their function in mediating chemoresistance has not been fully explored.
"Herein, we uncovered that pericytes potentiate DNA damage repair (DDR) in GBM cells residing in the perivascular niche, which induces temozolomide (TMZ) chemoresistance.
We found that increased pericyte proportion correlates with accelerated tumor recurrence and worse prognosis.
Genetic depletion of pericytes in GBM xenografts enhances TMZ-induced cytotoxicity and prolongs survival of tumor-bearing mice.
Mechanistically, C-C motif chemokine ligand 5 (CCL5) secreted by pericytes activates C-C motif chemokine receptor 5 (CCR5) on GBM cells to enable DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-mediated DDR upon TMZ treatment".
Disrupting CCL5-CCR5 paracrine signaling through the brain-penetrable CCR5 antagonist xxmaravirocxx (MVC) potently inhibits pericyte-promoted DDR and effectively improves the chemotherapeutic efficacy of TMZ. GBM patient-derived xenografts with high CCL5 expression benefit from combined treatment with TMZ and MVC.
Our study reveals the role of pericytes as an extrinsic stimulator potentiating DDR signaling in GBM cells and suggests that targeting CCL5-CCR5 signaling could be an effective therapeutic strategy to improve chemotherapeutic efficacy against GBM"
or the AI version
"Preclinical research indicates that
leronlimab (PRO 140), a humanized monoclonal antibody that acts as a C-C motif chemokine receptor 5 (CCR5) antagonist, enhances the cytotoxic effects of temozolomide (TMZ), particularly in cancer types where CCR5 signaling contributes to tumor progression and chemoresistance.
Key Findings on Leronlimab and Temozolomide Interaction:
Mechanism of Action: Leronlimab acts as a CCR5 antagonist, blocking the interaction between CCL5 (a chemokine) and its receptor CCR5, which is often exploited by tumor cells to survive DNA-damaging chemotherapy.
Overcoming Resistance: By targeting the CCL5-CCR5 axis, leronlimab is believed to inhibit pericyte-promoted DNA damage repair (DDR) in tumor cells, thereby mitigating resistance to TMZ.
Enhanced Cell Death: Studies have shown that blocking this pathway increases cell death induced by DNA-damaging chemotherapies like TMZ.
Preclinical Progress: As of March 2025, a preclinical study at the Albert Einstein College of Medicine is underway to analyze the sequencing of temozolomide and leronlimab
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