PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy

J Clin Invest. 2018 Apr 2;128(4):1413-1428. doi: 10.1172/JCI98047. Epub 2018 Mar 5.

Abstract

Intralesional therapy with oncolytic viruses (OVs) leads to the activation of local and systemic immune pathways, which may present targets for further combinatorial therapies. Here, we used human tumor histocultures as well as syngeneic tumor models treated with Newcastle disease virus (NDV) to identify a range of immune targets upregulated with OV treatment. Despite tumor infiltration of effector T lymphocytes in response to NDV, there was ongoing inhibition through programmed death ligand 1 (PD-L1), acting as a mechanism of early and late adaptive immune resistance to the type I IFN response and T cell infiltration, respectively. Systemic therapeutic targeting of programmed cell death receptor 1 (PD-1) or PD-L1 in combination with intratumoral NDV resulted in the rejection of both treated and distant tumors. These findings have implications for the timing of PD-1/PD-L1 blockade in conjunction with OV therapy and highlight the importance of understanding the adaptive mechanisms of immune resistance to specific OVs for the rational design of combinatorial approaches using these agents.

Keywords: Gene therapy; Immunology; Immunotherapy; Oncology; T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology*
  • Cell Line, Tumor
  • Humans
  • Immunotherapy*
  • Mice
  • Mice, Transgenic
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology*
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Oncolytic Virotherapy*
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology*

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Cd274 protein, mouse
  • Neoplasm Proteins
  • PDCD1 protein, human
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor