Replicating viral vector platform exploits alarmin signals for potent CD8 + T cell-mediated tumour immunotherapy

Nat Commun. 2017 May 26;8:15327. doi: 10.1038/ncomms15327.

Abstract

Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTLeff) responses. Conversely, the induction of protective tumour-specific CTLeff and their recruitment into the tumour remain challenging tasks. Here we show that lymphocytic choriomeningitis virus (LCMV) can be engineered to serve as a replication competent, stably-attenuated immunotherapy vector (artLCMV). artLCMV delivers tumour-associated antigens to dendritic cells for efficient CTL priming. Unlike replication-deficient vectors, artLCMV targets also lymphoid tissue stroma cells expressing the alarmin interleukin-33. By triggering interleukin-33 signals, artLCMV elicits CTLeff responses of higher magnitude and functionality than those induced by replication-deficient vectors. Superior anti-tumour efficacy of artLCMV immunotherapy depends on interleukin-33 signalling, and a massive CTLeff influx triggers an inflammatory conversion of the tumour microenvironment. Our observations suggest that replicating viral delivery systems can release alarmins for improved anti-tumour efficacy. These mechanistic insights may outweigh safety concerns around replicating viral vectors in cancer immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alarmins / immunology*
  • Animals
  • Antigens, Neoplasm / immunology
  • Cancer Vaccines / immunology*
  • Cancer Vaccines / therapeutic use
  • Cell Line, Tumor
  • Dendritic Cells / immunology
  • Gene Expression Profiling
  • Genetic Engineering
  • Genetic Vectors / genetics
  • Genetic Vectors / immunology
  • Genetic Vectors / therapeutic use
  • HEK293 Cells
  • Humans
  • Immunotherapy / methods*
  • Interleukin-33 / genetics
  • Interleukin-33 / immunology
  • Lymphocyte Activation / immunology
  • Lymphocytic choriomeningitis virus / genetics*
  • Mesocricetus
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • T-Lymphocytes, Cytotoxic / immunology*
  • Tumor Microenvironment / immunology
  • Vaccines, Live, Unattenuated / immunology
  • Virus Replication / genetics
  • Virus Replication / immunology
  • Xenograft Model Antitumor Assays

Substances

  • Alarmins
  • Antigens, Neoplasm
  • Cancer Vaccines
  • Il33 protein, mouse
  • Interleukin-33
  • Vaccines, Live, Unattenuated