Phenoscaping reveals multimodal γδ T cell cytotoxicity as a strategy to overcome cancer cell-mediated immunomodulation

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Callum Baird Nattress Rhianna O'Sullivan Daniel Fowler Colin Hutton Petra Vlckova Jahangir Sufi Magdalena Buschhaus Ewa Basiarz Maria Ramos Zapatero Ferran Cardoso Rodriguez Xiao Qin Ashley Campbell Angeliki Kanouta Vivian Li Kerry Chester John Anderson Marta Barisa Jonathan PH Fisher Christopher J Tape
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Abstract

γδ T cells can kill cancer cells via antibody-independent cytotoxicity (AIC) and antibody-dependent cellular cytotoxicity (ADCC). A better understanding of how these cytotoxic mechanisms are impacted by different cancer cells and different T cell donors could help identify improved immunotherapeutic strategies. To test the combinatorial interactions between T cell inter-donor heterogeneity (IDH), cancer cell inter-tumor heterogeneity (ITH), and multimodal γδ T cell killing, we performed a systematic single-cell phenoscaping analysis of >1,000 cultures of γδ T cells and colorectal cancer (CRC) patient-derived organoids (PDO). Phenoscaping analysis of post-translational modification (PTM) signaling, cell-cycle, apoptosis, and T cell immunophenotypes revealed that while unmodified γδ T cells have limited anti-tumor activity, IL-15Rα-IL-15 fusion protein (stIL15)-engineered γδ T cells can kill PDOs via AIC without exogenous cytokine support. However, when stIL15 γδ T cells only killed via AIC, cancer cells reciprocally rewired γδ T cell PTM signal networks in an ITH-specific manner to suppress anti-cancer cytotoxicity. stIL15 γδ T cells could overcome this cancer cell immunomodulation by also engaging B7-H3-targeted ADCC independent of B7-H3 checkpoint activity. Combined AIC and ADCC rescued γδ T cell PTM signaling flux and enabled γδ T cells to kill chemorefactory revival colon cancer stem cells. Together, these results demonstrate that multimodal γδ T cell cytoxicity mechanisms can overcome ITH-specific immunomodulation to kill chemorefractory cancer cells.

Journal details

Journal Cancer Research
Volume 85
Issue number 22
Pages 4415-4432
Available online
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Publisher website (DOI) 10.1158/0008-5472.CAN-25-1890
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Europe PubMed Central 40882026
Pubmed 40882026

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