Pharmacological tumor PDL1 depletion with chlorambucil treats ovarian cancer and melanoma: Improves antitumor immunity and renders anti-PDL1-resistant tumors anti-PDL1-sensitive through NK cell effects

Haiyan Bai, Alvaro S. Padron, Yilun Deng, Yiji J. Liao, Clare J. Murray, Carlos Ontiveros, Suresh J. Kari, Aravind Kancharla, Anand V.R. Kornepati, Myrna Garcia, Ryan Michael Reyes, Harshita B. Gupta, Jose R. Conejo-Garcia, Tyler Curiel

Research output: Contribution to journalArticlepeer-review

Abstract

Background Tumor intracellular programmed cell death ligand-1 (PDL1) mediates pathologic signals that regulate clinical treatment responses distinctly from surface-expressed PDL1 targeted by αPDL1 immune checkpoint blockade antibodies. Methods We performed a drug screen for tumor cell PDL1 depleting drugs that identified Food and Drug Administration (FDA)-approved chlorambucil and also 9-[2-(phosphonomethoxy)ethyl] guanine. We used in vitro and in vivo assays to evaluate treatment and signaling effects of pharmacological tumor PDL1 depletion focused on chlorambucil as FDA approved, alone or plus αPDL1. Results PDL1-expressing mouse and human ovarian cancer lines and mouse melanoma were more sensitive to chlorambucil-mediated proliferation inhibition in vitro versus corresponding genetically PDL1-depleted lines. Orthotopic peritoneal PDL1-expressing ID8agg ovarian cancer and subcutaneous B16 melanoma tumors were more chlorambucil-sensitive in vivo versus corresponding genetically PDL1-depleted tumors. Chlorambucil enhanced αPDL1 efficacy in tumors otherwise αPDL1-refractory, and improved antitumor immunity and treatment efficacy in a natural killer cell-dependent manner alone and plus αPDL1. Chlorambucil-mediated PDL1 depletion was relatively tumor-cell selective in vivo, and treatment efficacy was preserved in PDL1KO hosts, demonstrating tumor PDL1-specific treatment effects. Chlorambucil induced PDL1-dependent immunogenic tumor cell death which could help explain immune contributions. Chlorambucil-mediated PDL1 reduction mechanisms were tumor cell-type-specific and involved transcriptional or post-translational mechanisms, including promoting PDL1 ubiquitination through the GSK3β/β-TRCP pathway. Chlorambucil-mediated tumor cell PDL1 depletion also phenocopied genetic PDL1 depletion in reducing tumor cell mTORC1 activation and tumor initiating cell content, and in augmenting autophagy, suggesting additional treatment potential. Conclusions Pharmacological tumor PDL1 depletion with chlorambucil targets tumor-intrinsic PDL1 signaling that mediates treatment resistance, especially in αPDL1-resistant tumors, generates PDL1-dependent tumor immunogenicity and inhibits tumor growth in immune-dependent and independent manners. It could improve treatment efficacy of selected agents in otherwise treatment-refractory, including αPDL1-refractory cancers, and is rapidly clinically translatable.

Original languageEnglish (US)
Article numbere004871
JournalJournal for ImmunoTherapy of Cancer
Volume11
Issue number2
DOIs
StatePublished - Feb 9 2023

Keywords

  • Combined Modality Therapy
  • Costimulatory and Inhibitory T-Cell Receptors
  • Drug Evaluation, Preclinical
  • Immunotherapy
  • Melanoma

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Immunology and Allergy
  • Pharmacology
  • Immunology

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