dataset
posted on 2025-11-14, 08:24 authored by 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 S.W. Li, Kerry Chester, John Anderson, Marta Barisa, Jonathan P.H. Fisher, Christopher J. Tape <p>Flow cytometry reagents for γδT cell phenotyping</p>
Funding
Cancer Research UK (CRUK)
Medical Research Council (MRC)
UCLH Biomedical Research Centre (UCL)
Academy of Medical Sciences (The Academy of Medical Sciences)
National Institute for Health and Care Research (NIHR)
University College London (UCL)
Little Princess Trust (LPT)
Great Ormond Street Hospital Charity (GOSH)
Wellcome Trust (WT)
History
ARTICLE 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 affected by different cancer cells and different T-cell donors could help identify improved immunotherapeutic strategies. To test the combinatorial interactions among T cell interdonor heterogeneity, cancer cell intertumor heterogeneity (ITH), and multimodal γδ T-cell killing, we performed a systematic single-cell phenoscaping analysis of more than 1,000 γδ T-cell and colorectal cancer patient-derived organoid cultures. Single-cell analysis of posttranslational modification (PTM) signaling, cell cycle, apoptosis, and T-cell immunophenotypes revealed that whereas unmodified γδ T cells have limited antitumor activity, IL15Rα–IL15 fusion protein [stabilized IL15 (stIL15)]-engineered γδ T cells can kill patient-derived organoids 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 anticancer 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.
Single-cell phenoscaping of more than 1,000 γδ T-cell and patient-derived organoid cultures shows that cancer cells suppress anticancer γδ T-cell cytotoxicity but γδ T cells can use multimodal killing to overcome immunomodulation.
