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

Publication ,  Journal Article
Murray, C; Galvan, E; Ontiveros, C; Deng, Y; Bai, H; Padron, AS; Hinchee-Rodriguez, K; Garcia, MG; Kornepati, A; Conejo-Garcia, J; Curiel, TJ
Published in: Int J Mol Sci
May 4, 2022

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.

Duke Scholars

Published In

Int J Mol Sci

DOI

EISSN

1422-0067

Publication Date

May 4, 2022

Volume

23

Issue

9

Location

Switzerland

Related Subject Headings

  • Mice
  • Melanoma
  • DNA Damage
  • Chemical Physics
  • Ceftazidime
  • Cefepime
  • B7-H1 Antigen
  • Animals
  • 3404 Medicinal and biomolecular chemistry
  • 3107 Microbiology
 

Citation

APA
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ICMJE
MLA
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Murray, C., Galvan, E., Ontiveros, C., Deng, Y., Bai, H., Padron, A. S., … Curiel, T. J. (2022). Pharmacologic Tumor PDL1 Depletion with Cefepime or Ceftazidime Promotes DNA Damage and Sensitivity to DNA-Damaging Agents. Int J Mol Sci, 23(9). https://doi.org/10.3390/ijms23095129
Murray, Clare, Eva Galvan, Carlos Ontiveros, Yilun Deng, Haiyan Bai, Alvaro Souto Padron, Kathryn Hinchee-Rodriguez, et al. “Pharmacologic Tumor PDL1 Depletion with Cefepime or Ceftazidime Promotes DNA Damage and Sensitivity to DNA-Damaging Agents.Int J Mol Sci 23, no. 9 (May 4, 2022). https://doi.org/10.3390/ijms23095129.
Murray C, Galvan E, Ontiveros C, Deng Y, Bai H, Padron AS, et al. Pharmacologic Tumor PDL1 Depletion with Cefepime or Ceftazidime Promotes DNA Damage and Sensitivity to DNA-Damaging Agents. Int J Mol Sci. 2022 May 4;23(9).
Murray, Clare, et al. “Pharmacologic Tumor PDL1 Depletion with Cefepime or Ceftazidime Promotes DNA Damage and Sensitivity to DNA-Damaging Agents.Int J Mol Sci, vol. 23, no. 9, May 2022. Pubmed, doi:10.3390/ijms23095129.
Murray C, Galvan E, Ontiveros C, Deng Y, Bai H, Padron AS, Hinchee-Rodriguez K, Garcia MG, Kornepati A, Conejo-Garcia J, Curiel TJ. Pharmacologic Tumor PDL1 Depletion with Cefepime or Ceftazidime Promotes DNA Damage and Sensitivity to DNA-Damaging Agents. Int J Mol Sci. 2022 May 4;23(9).

Published In

Int J Mol Sci

DOI

EISSN

1422-0067

Publication Date

May 4, 2022

Volume

23

Issue

9

Location

Switzerland

Related Subject Headings

  • Mice
  • Melanoma
  • DNA Damage
  • Chemical Physics
  • Ceftazidime
  • Cefepime
  • B7-H1 Antigen
  • Animals
  • 3404 Medicinal and biomolecular chemistry
  • 3107 Microbiology