Abstract 4102: attIL12-T cell therapy destructs cancer-associated fibroblasts and extracellular matrix in heterogenous osteosarcoma xenograft models

Abstract

Abstract 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 CAR-T cell therapy does not impair ECM components such as collagen. In this study, we investigated whether the recently invented attIL12-T cells could destroy CAFs to disrupt the ECM and uncovered the underlying mechanism by which attIL12-T cells penetrate stroma-enriched osteosarcoma tumors. 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 that CAF/ECM density was inversely correlated with T-cell infiltration. Other IL12-armed T cells, such as wild-type IL12-T or ttIL12-T cells, did not disrupt the ECM because this effect depended on the engagement between cell-surface vimentin (CSV) on the tumor cell surface and its ligand on the attIL12 -T cells. Mechanistic studies found that attIL12-T cell treatment elevated IFNγ production upon interacting with CSV+ tumor cells to suppress TGFβ secretion and in turn upregulate FAS-mediated CAF apoptosis. CAF destruction reshaped the tumor stroma to favor T cell infiltration and tumor destruction. Thus, 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. Citation Format: Jiemiao Hu, Alexander Lazar, Davis Ingram, Wei-Lien Wang, Wendong Zhang, Zhiliang Jia, Dristhi Ragoonanan, Jian Wang, Xueqing Xia, Kris Mahadeo, Richard Gorlick, Shulin Li. attIL12-T cell therapy destructs cancer-associated fibroblasts and extracellular matrix in heterogenous osteosarcoma xenograft models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4102.