Targeting IGF2 To Reprogram the Tumor Microenvironment for Enhanced Viro-Immunotherapy

Authors

Min Hye Noh
Jin Muk Kang
Alexandra A Miller
Grace Nguyen
Minxin Huang
Ji Seon Shim
Alberto J Bueso-Perez
Sara A Murphy
Kimberly A Rivera-Caraballo
Yoshihiro Otani
Eunju Kim
Seung-Hee Yoo
Yuanqing Yan
Yeshavanth Banasavadi-Siddegowda
Hiroshi Nakashima
E Antonio Chiocca
Balveen Kaur
Zhongming Zhao
Tae Jin Lee
Ji Young Yoo

Publication Date

9-5-2024

Journal

Neuro-Oncology

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

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

Comments

Supplementary Materials

PMID: 38853689