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

Autor: Hernández-López P; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., van Diest E; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Brazda P; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Heijhuurs S; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Meringa A; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Hoorens van Heyningen L; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Riillo C; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.; Department of Experimental and Clinical Medicine, Magna Græcia University, Catanzaro, Italy., Schwenzel C; Faculty of Biology, University of Freiburg, Freiburg, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.; Center of Chronic Immunodeficiency (CCI) and Institute for Immunodeficiency, University Clinics and Medical Faculty, Freiburg, Germany., Zintchenko M; Faculty of Biology, University of Freiburg, Freiburg, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.; Center of Chronic Immunodeficiency (CCI) and Institute for Immunodeficiency, University Clinics and Medical Faculty, Freiburg, Germany., Johanna I; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Nicolasen MJT; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Cleven A; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Kluiver TA; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Millen R; Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, the Netherlands., Zheng J; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Karaiskaki F; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Straetemans T; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Clevers H; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.; Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, the Netherlands.; Roche Pharmaceutical Research and Early Development, Basel, Switzerland., de Bree R; Department of Head and Neck Surgical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands., Stunnenberg HG; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Peng WC; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands., Roodhart J; Department of Medical Oncology, University Medical Center Utrecht, Utrecht, the Netherlands., Minguet S; Faculty of Biology, University of Freiburg, Freiburg, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.; Center of Chronic Immunodeficiency (CCI) and Institute for Immunodeficiency, University Clinics and Medical Faculty, Freiburg, Germany., Sebestyén Z; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Beringer DX; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Kuball J; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. j.h.e.kuball@umcutrecht.nl.; Department of Hematology, University Medical Center Utrecht, Utrecht, the Netherlands. j.h.e.kuball@umcutrecht.nl.
Jazyk: angličtina
Zdroj: Nature immunology [Nat Immunol] 2024 Jan; Vol. 25 (1), pp. 88-101. Date of Electronic Publication: 2023 Nov 27.
DOI: 10.1038/s41590-023-01665-0
Abstrakt: 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-CD28 WT chimera enabled control only of liquid tumors, whereas the NKG2D-4-1BB CD28TM 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-4-1BB CD28TM and 103-4-1BB chimeras reprogram TEGs through NF-κB. Owing to competition with naturally expressed NKG2D in CD8 + TEGs, the NKG2D-4-1BB CD28TM 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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