Adoptive transfer of membrane-anchored and tumor cell surface vimentin-targeted interleukin 12 armed TILs suppresses collagen expression to boost deep T-cell tumor infiltration 2033

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Abstract Description Tumor-targeted T-cell therapies is limited by its inability to penetrate the collagen barrier surrounding tumors. Our previously reported cell surface vimentin (CSV)–targeted and membrane-anchored IL12-armed (attIL12) T cells can reduce collagen production by killing cancer-associated fibroblasts but cannot reduce collagen expression by tumors that highly express CCKAR. In this study, we discovered that attIL12-modified tumor-infiltrating lymphocytes (TILs) disabled collagen production by CCKAR-high autologous tumor cells in vitro and sarcoma patient-derived xenografts (PDXs) in vivo. This disruption of collagen production by tumor cells required a simultaneous interaction between the CSV on autologous tumor cells, which is targeted by attIL12, and HLA-TCR on attIL12-TILs; when either interaction was abrogated, collagen production was not shut down. Mechanistically, the interaction between attIL12-TILs and autologous tumor cells synergized IFNγ production, which in combination with CCKAR downregulation reduced collagen expression through suppression of both TGFβ-stimulated SMAD activation and CCKAR-AKT signaling. Diminishing collagen expression from tumor cells significantly increased T-cell infiltration and improved tumor growth inhibition in PDX sarcomas. This study thus uncovers the first tumor collagen–disrupting T-cell therapy we know of. Thus, this attIL12-TIL therapy holds great clinical potential for boosting T-cell infiltration in high-grade, collagen-rich tumors. Funding Sources This study was supported by the National Institutes of Health through grant R01 CA200574 and Cancer Center Support Grant P30 CA016672. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

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