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Dual targeting of cancer metabolome and stress antigens affects transcriptomic heterogeneity and efficacy of engineered T cells

Patricia Hernández-López, Eline van Diest, Peter Brazda, Sabine Heijhuurs, Angelo Meringa, Lauren Hoorens van Heyningen, Caterina Riillo, Caroline Schwenzel, Marina Zintchenko, Inez Johanna, Mara J. T. Nicolasen, Astrid Cleven, Thomas A. Kluiver, Rosemary Millen, Jiali Zheng, Froso Karaiskaki, Trudy Straetemans, Hans Clevers, Remco de Bree, Hendrik G. Stunnenberg, Weng Chuan Peng, Jeanine Roodhart, Susana Minguet, Zsolt Sebestyén, Dennis X. Beringer & Jürgen Kuball

Published: January 2024

Few cancers can be targeted efficiently by engineered T cell strategies. Here, we show that γδ T cell antigen receptor (γδ TCR)-mediated cancer metabolome targeting can be combined with targeting of cancer-associated stress antigens (such as NKG2D ligands or CD277) through the addition of chimeric co-receptors. This strategy overcomes suboptimal γ9δ2 TCR engagement of αβ T cells engineered to express a defined γδ TCR (TEGs) and improves serial killing, proliferation and persistence of TEGs. In vivo, the NKG2D-CD28WT chimera enabled control only of liquid tumors, whereas the NKG2D-4-1BBCD28TM chimera prolonged persistence of TEGs and improved control of liquid and solid tumors. The CD277-targeting chimera (103-4-1BB) was the most optimal co-stimulation format, eradicating both liquid and solid tumors. Single-cell transcriptomic analysis revealed that NKG2D-4-1BBCD28TM and 103-4-1BB chimeras reprogram TEGs through NF-κB. Owing to competition with naturally expressed NKG2D in CD8+ TEGs, the NKG2D-4-1BBCD28TM chimera mainly skewed CD4+ TEGs toward adhesion, proliferation, cytotoxicity and less exhausted signatures, whereas the 103-4-1BB chimera additionally shaped the CD8+ subset toward a proliferative state.

Full Access Link: Nature Immunology