Targeting IGF2 to reprogram the tumor microenvironment for enhanced viro-immunotherapy

Neuro Oncol. 2024 Sep 5;26(9):1602-1616. doi: 10.1093/neuonc/noae105.

Abstract

Background: The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME).

Methods: RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance.

Results: Transcriptome analysis identified IGF2 as one of the top-secreted proteins following oHSV treatment. Moreover, IGF2 expression was significantly upregulated in 10 out of 14 recurrent GBM patients after treatment with oHSV, rQNestin34.5v.2 (71.4%; P = .0020) (ClinicalTrials.gov, NCT03152318). Depletion of IGF2 substantially enhanced oHSV-mediated tumor cell killing in vitro and improved survival of mice bearing BCBM tumors in vivo. To mitigate the oHSV-induced IGF2 in the TME, we constructed a novel oHSV, oHSV-D11mt, secreting a modified IGF2R domain 11 (IGF2RD11mt) that acts as IGF2 decoy receptor. Selective blocking of IGF2 by IGF2RD11mt significantly increased cytotoxicity, reduced oHSV-induced neutrophils/PMN-MDSCs infiltration, and reduced secretion of immune suppressive/proangiogenic cytokines, while increased CD8 + cytotoxic T lymphocytes (CTLs) infiltration, leading to enhanced survival in GBM or BCBM tumor-bearing mice.

Conclusions: This is the first study reporting that oHSV-induced secreted IGF2 exerts a critical role in resistance to oHSV therapy, which can be overcome by oHSV-D11mt as a promising therapeutic advance for enhanced viro-immunotherapy.

Keywords: Oncolytic herpes simplex virus-1 (oHSV); glioblastoma (GBM); insulin-like growth factor 2 (IGF2); insulin-like growth factor-1 receptor (IGF1R); tumor microenvironment (TME).

Publication types

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

MeSH terms

  • Animals
  • Brain Neoplasms* / immunology
  • Brain Neoplasms* / metabolism
  • Brain Neoplasms* / pathology
  • Brain Neoplasms* / therapy
  • Breast Neoplasms / immunology
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy
  • Female
  • Glioblastoma / immunology
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Glioblastoma / therapy
  • Glioma / immunology
  • Glioma / metabolism
  • Glioma / pathology
  • Glioma / therapy
  • Herpesvirus 1, Human
  • Humans
  • Immunotherapy* / methods
  • Insulin-Like Growth Factor II* / antagonists & inhibitors
  • Insulin-Like Growth Factor II* / genetics
  • Insulin-Like Growth Factor II* / metabolism
  • Mice
  • Oncolytic Virotherapy* / methods
  • Oncolytic Viruses
  • Tumor Cells, Cultured
  • Tumor Microenvironment* / immunology
  • Xenograft Model Antitumor Assays

Substances

  • IGF2 protein, human
  • Insulin-Like Growth Factor II

Associated data

  • ClinicalTrials.gov/NCT03152318