PD-L1 + aneuploid circulating tumor endothelial cells (CTECs) exhibit resistance to the checkpoint blockade immunotherapy in advanced NSCLC patients

Cancer Lett. 2020 Jan 28;469:355-366. doi: 10.1016/j.canlet.2019.10.041. Epub 2019 Oct 31.

Abstract

Sustained angiogenesis and increased PD-L1 expression on endothelial and carcinoma cells contribute toward fostering an immunosuppressive microenvironment suitable for tumor growth. PD-L1+ CTCs were reported to associate with poor prognosis in NSCLC patients. However, whether or not aneuploid circulating tumor endothelial cells (CTECs) express PD-L1, then serve as a surrogate biomarker to evaluate immunotherapy efficacy remains unknown. In this study, a novel SE-iFISH strategy was established to comprehensively quantify and characterize a full spectrum of aneuploid CTCs and CTECs in advanced NSCLC patients subjected to second-line anti-PD-1 (nivolumab) immunotherapy. In situ co-detection of diverse subtypes of aneuploid CTCs and CTECs expressing PD-L1 and Vimentin was performed. The present clinical study demonstrated that significant amounts of PD-L1+ aneuploid CTCs and CTECs could be detected in histopathologic hPD-L1- patients. In contrast to decreased PD-L1+ CTCs, the number of multiploid PD-L1+ CTECs (≥tetrasomy 8) undergoing post-therapeutic karyotype shifting increased in patients along with tumor progression following anti-PD-1 treatment. Progressive disease (PD) lung cancer patients possessing multiploid PD-L1+ CTECs had a significantly shorter PFS compared to those without PD-L1+ CTECs. In carcinoma patients, aneuploid CTCs and CTECs may exhibit a functional interplay with respect to tumor angiogenesis, progression, metastasis, and response to immunotherapy.

Keywords: Aneuploid CTC and CTEC; Cellular circulating tumor biomarker; Liquid biopsy; Post-therapeutic karyotype shifting; SE-iFISH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aneuploidy
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / genetics*
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / immunology
  • Carcinoma, Non-Small-Cell Lung / blood
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Disease Progression
  • Drug Resistance, Neoplasm / immunology
  • Endothelial Cells / immunology
  • Female
  • Humans
  • Immunotherapy
  • Male
  • Middle Aged
  • Neoplastic Cells, Circulating / immunology*
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / immunology
  • Neovascularization, Pathologic / pathology
  • Nivolumab / administration & dosage
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / genetics
  • Progression-Free Survival
  • Tumor Microenvironment / immunology

Substances

  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Nivolumab