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Pharmacologic Tumor PDL1 Depletion with Cefepime or Ceftazidime Promotes DNA Damage and Sensitivity to DNA-Damaging Agents

The interaction between tumor surface-expressed PDL1 and immune cell PD1 for the evasion of antitumor immunity is well established and is targeted by FDA-approved anti-PDL1 and anti-PD1 antibodies. Nonetheless, recent studies highlight the immunopathogenicity of tumor-intrinsic PDL1 signals that can...

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Autores principales: Murray, Clare, Galvan, Eva, Ontiveros, Carlos, Deng, Yilun, Bai, Haiyan, Padron, Alvaro Souto, Hinchee-Rodriguez, Kathryn, Garcia, Myrna G., Kornepati, Anand, Conejo-Garcia, Jose, Curiel, Tyler J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9099860/
https://www.ncbi.nlm.nih.gov/pubmed/35563520
http://dx.doi.org/10.3390/ijms23095129
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author Murray, Clare
Galvan, Eva
Ontiveros, Carlos
Deng, Yilun
Bai, Haiyan
Padron, Alvaro Souto
Hinchee-Rodriguez, Kathryn
Garcia, Myrna G.
Kornepati, Anand
Conejo-Garcia, Jose
Curiel, Tyler J.
author_facet Murray, Clare
Galvan, Eva
Ontiveros, Carlos
Deng, Yilun
Bai, Haiyan
Padron, Alvaro Souto
Hinchee-Rodriguez, Kathryn
Garcia, Myrna G.
Kornepati, Anand
Conejo-Garcia, Jose
Curiel, Tyler J.
author_sort Murray, Clare
collection PubMed
description The interaction between tumor surface-expressed PDL1 and immune cell PD1 for the evasion of antitumor immunity is well established and is targeted by FDA-approved anti-PDL1 and anti-PD1 antibodies. Nonetheless, recent studies highlight the immunopathogenicity of tumor-intrinsic PDL1 signals that can contribute to the resistance to targeted small molecules, cytotoxic chemotherapy, and αPD1 immunotherapy. As genetic PDL1 depletion is not currently clinically tractable, we screened FDA-approved drugs to identify those that significantly deplete tumor PDL1. Among the candidates, we identified the β-lactam cephalosporin antibiotic cefepime as a tumor PDL1-depleting drug (PDD) that increases tumor DNA damage and sensitivity to DNA-damaging agents in vitro in distinct aggressive mouse and human cancer lines, including glioblastoma multiforme, ovarian cancer, bladder cancer, and melanoma. Cefepime reduced tumor PDL1 post-translationally through ubiquitination, improved DNA-damaging-agent treatment efficacy in vivo in immune-deficient and -proficient mice, activated immunogenic tumor STING signals, and phenocopied specific genetic PDL1 depletion effects. The β-lactam ring and its antibiotic properties did not appear contributory to PDL1 depletion or to these treatment effects, and the related cephalosporin ceftazidime produced similar effects. Our findings highlight the rapidly translated potential for PDDs to inhibit tumor-intrinsic PDL1 signals and improve DNA-damaging agents and immunotherapy efficacy.
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spelling pubmed-90998602022-05-14 Pharmacologic Tumor PDL1 Depletion with Cefepime or Ceftazidime Promotes DNA Damage and Sensitivity to DNA-Damaging Agents Murray, Clare Galvan, Eva Ontiveros, Carlos Deng, Yilun Bai, Haiyan Padron, Alvaro Souto Hinchee-Rodriguez, Kathryn Garcia, Myrna G. Kornepati, Anand Conejo-Garcia, Jose Curiel, Tyler J. Int J Mol Sci Article The interaction between tumor surface-expressed PDL1 and immune cell PD1 for the evasion of antitumor immunity is well established and is targeted by FDA-approved anti-PDL1 and anti-PD1 antibodies. Nonetheless, recent studies highlight the immunopathogenicity of tumor-intrinsic PDL1 signals that can contribute to the resistance to targeted small molecules, cytotoxic chemotherapy, and αPD1 immunotherapy. As genetic PDL1 depletion is not currently clinically tractable, we screened FDA-approved drugs to identify those that significantly deplete tumor PDL1. Among the candidates, we identified the β-lactam cephalosporin antibiotic cefepime as a tumor PDL1-depleting drug (PDD) that increases tumor DNA damage and sensitivity to DNA-damaging agents in vitro in distinct aggressive mouse and human cancer lines, including glioblastoma multiforme, ovarian cancer, bladder cancer, and melanoma. Cefepime reduced tumor PDL1 post-translationally through ubiquitination, improved DNA-damaging-agent treatment efficacy in vivo in immune-deficient and -proficient mice, activated immunogenic tumor STING signals, and phenocopied specific genetic PDL1 depletion effects. The β-lactam ring and its antibiotic properties did not appear contributory to PDL1 depletion or to these treatment effects, and the related cephalosporin ceftazidime produced similar effects. Our findings highlight the rapidly translated potential for PDDs to inhibit tumor-intrinsic PDL1 signals and improve DNA-damaging agents and immunotherapy efficacy. MDPI 2022-05-04 /pmc/articles/PMC9099860/ /pubmed/35563520 http://dx.doi.org/10.3390/ijms23095129 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Murray, Clare
Galvan, Eva
Ontiveros, Carlos
Deng, Yilun
Bai, Haiyan
Padron, Alvaro Souto
Hinchee-Rodriguez, Kathryn
Garcia, Myrna G.
Kornepati, Anand
Conejo-Garcia, Jose
Curiel, Tyler J.
Pharmacologic Tumor PDL1 Depletion with Cefepime or Ceftazidime Promotes DNA Damage and Sensitivity to DNA-Damaging Agents
title Pharmacologic Tumor PDL1 Depletion with Cefepime or Ceftazidime Promotes DNA Damage and Sensitivity to DNA-Damaging Agents
title_full Pharmacologic Tumor PDL1 Depletion with Cefepime or Ceftazidime Promotes DNA Damage and Sensitivity to DNA-Damaging Agents
title_fullStr Pharmacologic Tumor PDL1 Depletion with Cefepime or Ceftazidime Promotes DNA Damage and Sensitivity to DNA-Damaging Agents
title_full_unstemmed Pharmacologic Tumor PDL1 Depletion with Cefepime or Ceftazidime Promotes DNA Damage and Sensitivity to DNA-Damaging Agents
title_short Pharmacologic Tumor PDL1 Depletion with Cefepime or Ceftazidime Promotes DNA Damage and Sensitivity to DNA-Damaging Agents
title_sort pharmacologic tumor pdl1 depletion with cefepime or ceftazidime promotes dna damage and sensitivity to dna-damaging agents
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9099860/
https://www.ncbi.nlm.nih.gov/pubmed/35563520
http://dx.doi.org/10.3390/ijms23095129
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