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 StunnenbergWeng Chuan Peng, Jeanine Roodhart, Susana Minguet, Zsolt Sebestyén, Dennis X Beringer, Jürgen Kuball

Research output: Contribution to journal/periodicalArticleScientificpeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalNature Immunology
DOIs
Publication statusE-pub ahead of print - 27 Nov 2023

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