IL-27 gene therapy induces depletion of Tregs and enhances the efficacy of cancer immunotherapy

JCI Insight. 2018 Apr 5;3(7):e98745. doi: 10.1172/jci.insight.98745.

Abstract

Tumor-induced expansion of Tregs is a significant obstacle to cancer immunotherapy. However, traditional approaches to deplete Tregs are often inefficient, provoking autoimmunity. We show here that administration of IL-27-expressing recombinant adeno-associated virus (AAV-IL-27) significantly inhibits tumor growth and enhances T cell responses in tumors. Strikingly, we found that AAV-IL-27 treatment causes rapid depletion of Tregs in peripheral blood, lymphoid organs, and - most pronouncedly - tumor microenvironment. AAV-IL-27-mediated Treg depletion is dependent on IL-27 receptor and Stat1 in Tregs and is a combined result of CD25 downregulation in Tregs and inhibition of IL-2 production by T cells. In combination with a GM-CSF vaccine, AAV-IL-27 treatment not only induced nearly complete tumor rejection, but also resulted in amplified neoantigen-specific T cell responses. AAV-IL-27 also dramatically increased the efficacy of anti-PD-1 therapy, presumably due to induction of PD-L1 in T cells and depletion of Tregs. Importantly, AAV-IL-27 therapy did not induce significant adverse events, partially due to its induction of IL-10. In a plasmacytoma mouse model, we found that IL-10 was required for AAV-IL-27-mediated tumor rejection. Thus, our study demonstrates the potential of AAV-IL-27 as an independent cancer therapeutic and as an efficient adjuvant for cancer immunotherapy.

Keywords: Adaptive immunity; Cytokines; Immunology; Oncology; T cells.

Publication types

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

MeSH terms

  • Animals
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / immunology
  • Cell Line, Tumor / transplantation
  • Dependovirus / genetics
  • Disease Models, Animal
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology
  • Humans
  • Interleukin-10 / genetics
  • Interleukin-10 / immunology
  • Interleukin-10 / metabolism
  • Interleukins / genetics*
  • Interleukins / immunology
  • Lymphocyte Depletion / methods*
  • Mice
  • Mice, Knockout
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Treatment Outcome
  • Tumor Microenvironment / immunology

Substances

  • Cancer Vaccines
  • IL10 protein, mouse
  • Il27 protein, mouse
  • Interleukins
  • Recombinant Proteins
  • Interleukin-10
  • Granulocyte-Macrophage Colony-Stimulating Factor