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  2. 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

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

  • J Immunother Cancer. 2023 Feb;11(2):e004871. doi: 10.1136/jitc-2022-004871.
Haiyan Bai 1 Alvaro S Padron 2 Yilun Deng 2 Yiji J Liao 1 Clare J Murray 3 4 Carlos Ontiveros 1 4 Suresh J Kari 1 Aravind Kancharla 5 Anand V R Kornepati 4 Myrna Garcia 4 6 Ryan Michael Reyes 4 6 7 Harshita B Gupta 2 Jose R Conejo-Garcia 8 Tyler Curiel 9 4 6 10
Affiliations

Affiliations

  • 1 Department of Medicine, University of Texas Health, San Antonio, Texas, USA.
  • 2 Department of Medicine, University of Texas Health Science Center, San Antonio, Texas, USA.
  • 3 Medicine, University of Texas Health, San Antonio, Texas, USA.
  • 4 The Graduate School of Biomedical Sciences, UTHSCSA, San Antonio, Texas, USA.
  • 5 Med Hematology/Oncology, UT Health Long School of Medicine, San Antonio, Texas, USA.
  • 6 UT Health Long School of Medicine, San Antonio, Texas, USA.
  • 7 Division of Hematology/Medical Oncology, UT Health Long School of Medicine, San Antonio, Texas, USA.
  • 8 Department of Immunology, Duke School of Medicine, Durham, NC, USA.
  • 9 Department of Medicine, University of Texas Health, San Antonio, Texas, USA tyler.j.curiel@dartmouth.edu.
  • 10 Medicine, University of Texas Health Science Center, San Antonio, Texas, USA.
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.

Keywords

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

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