Cell Membrane-Anchored and Tumor-Targeted Il-12 T-cell Therapy Destroys Cancer-Associated Fibroblasts and Disrupts Extracellular Matrix in Heterogenous Osteosarcoma Xenograft Models

Authors

Jiemiao Hu
Alexander J Lazar
Davis Ingram
Wei-Lien Wang
Wendong Zhang
Zhiliang Jia
Dristhi Ragoonanan
Jian Wang
Xueqing Xia
Kris Mahadeo
Richard Gorlick
Shulin Li

Publication Date

1-9-2024

Journal

The Journal for ImmunoTherapy of Cancer

Abstract

Background: The extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) play major roles in tumor progression, metastasis, and the poor response of many solid tumors to immunotherapy. CAF-targeted chimeric antigen receptor-T cell therapy cannot infiltrate ECM-rich tumors such as osteosarcoma.

Method: In this study, we used RNA sequencing to assess whether the recently invented membrane-anchored and tumor-targeted IL-12-armed (attIL12) T cells, which bind cell-surface vimentin (CSV) on tumor cells, could destroy CAFs to disrupt the ECM. We established an in vitro model of the interaction between osteosarcoma CAFs and attIL12-T cells to uncover the underlying mechanism by which attIL12-T cells penetrate stroma-enriched osteosarcoma tumors.

Results: RNA sequencing demonstrated that attIL12-T cell treatment altered ECM-related gene expression. Immunohistochemistry staining revealed disruption or elimination of high-density CAFs and ECM in osteosarcoma xenograft tumors following attIL12-T cell treatment, and CAF/ECM density was inversely correlated with T-cell infiltration. Other IL12-armed T cells, such as wild-type IL-12-targeted or tumor-targeted IL-12-T cells, did not disrupt the ECM because this effect depended on the engagement between CSV on the tumor cell and its ligand on the attIL12-T cells. Mechanistic studies found that attIL12-T cell treatment elevated IFNγ production on interacting with CSV+ tumor cells, suppressing transforming growth factor beta secretion and in turn upregulating FAS-mediated CAF apoptosis. CAF destruction reshaped the tumor stroma to favor T-cell infiltration and tumor inhibition.

Conclusions: This study unveiled a novel therapy-attIL12-T cells-for targeting CAFs/ECM. These findings are highly relevant to humans because CAFs are abundant in human osteosarcoma.

Keywords

Animals, Humans, Interleukin-12, Cancer-Associated Fibroblasts, Heterografts, Osteosarcoma, Cell Membrane, Extracellular Matrix, Disease Models, Animal, Bone Neoplasms, Cell- and Tissue-Based Therapy

DOI

10.1136/jitc-2023-006991

PMID

38199607

PMCID

PMC10806671

PubMedCentral® Posted Date

1-10-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes