T cell–mediated antibody-dependent cellular cytotoxicity provides a therapeutic approach for solid cancers

The clinical success of chimeric antigen receptor T cells in treating hematological malignancies has highlighted the immense therapeutic potential of engineering T cells with synthetic receptors. However, the limited availability of tumor-specific antigens and the poor ability of T cells to infiltrate solid tumor cores remain major obstacles for applying this approach to solid tumors. In this study, we identify a subset of CD8+ T cells at inflammatory sites that acquire FcγRI through trogocytosis from infiltrating monocytes, enabling them to perform transient TCR-independent antibody-dependent cellular cytotoxicity (ADCC). Analysis of FcγRI signaling in these T cells revealed that phosphorylation occurs only when antigen density on the membrane exceeds 30 molecules/μm². Exploiting this threshold, we engineered peripheral blood CD8+ T cells to express a modified FcγRI receptor, allowing them to selectively kill tumor cells while largely sparing healthy tissues expressing normal physiological levels of the same antigen. Moreover, expression of FcγRI receptor in T cells was associated with reduced basement membrane interactions, enhancing their capacity to infiltrate tumors and establish long-term immune memory. Collectively, this work establishes T cell-mediated ADCC as a potent therapeutic strategy that leverages antigen density, rather than antigen identity, to achieve selective cancer targeting.

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Publication Details

Journal
JCI Insight
Published
2026-11-08
DOI
https://doi.org/10.1172/jci.insight.205984
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
0.00

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article

T cell–mediated antibody-dependent cellular cytotoxicity provides a therapeutic approach for solid cancers

Matthew H. Spitzer, Raya Sorkin, Ariel Galor, Carmit Levy et al.
2 links
JCI Insight
CAR-T cell therapy research
article

T cell–mediated antibody-dependent cellular cytotoxicity provides a therapeutic approach for solid cancers

Matthew H. Spitzer, Raya Sorkin, Ariel Galor, Carmit Levy, Yaron Carmi, Natalia Tarnovitski Freund, Peleg Rider, Eran Sadot, Nadine Santana-Magal, Michael Loran Dustin, Oran Zlotnik, Merav Cohen, Alexander Leithner, Diana Rasoulouniriana, Petr Shendrik, Ori Moskowitz, Avishai Maliah, Tom Ben‐Dov, Shahar Dotan, Maya Halpern, Amichai Zarfin, Aseel Khateeb, Yu Zhang, Alon Richter, Chen Luxenburg, Gal Verbin, Adi Frisch
article en

Abstract

The clinical success of chimeric antigen receptor T cells in treating hematological malignancies has highlighted the immense therapeutic potential of engineering T cells with synthetic receptors. However, the limited availability of tumor-specific antigens and the poor ability of T cells to infiltrate solid tumor cores remain major obstacles for applying this approach to solid tumors. In this study, we identify a subset of CD8+ T cells at inflammatory sites that acquire FcγRI through trogocytosis from infiltrating monocytes, enabling them to perform transient TCR-independent antibody-dependent cellular cytotoxicity (ADCC). Analysis of FcγRI signaling in these T cells revealed that phosphorylation occurs only when antigen density on the membrane exceeds 30 molecules/μm². Exploiting this threshold, we engineered peripheral blood CD8+ T cells to express a modified FcγRI receptor, allowing them to selectively kill tumor cells while largely sparing healthy tissues expressing normal physiological levels of the same antigen. Moreover, expression of FcγRI receptor in T cells was associated with reduced basement membrane interactions, enhancing their capacity to infiltrate tumors and establish long-term immune memory. Collectively, this work establishes T cell-mediated ADCC as a potent therapeutic strategy that leverages antigen density, rather than antigen identity, to achieve selective cancer targeting.

JCI InsightVol. 11(21)
Gladstone Institutes (US), Tel Aviv University (IL), University of California, San Francisco (US), Rabin Medical Center (IL), Meir Medical Center (IL), University of Oxford (GB), University of California San Francisco Medical Center (US), Kennedy Institute of Rheumatology (GB)
Israel Science Foundation
Good health and well-being
CAR-T cell therapy research
DOIOpen Access PDFOpenAlex
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