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

doi:10.1038/s41590-023-01665-0

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

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

2 Citaten (Scopus)

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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.

Originele taal-2	Engels
Tijdschrift	Nature Immunology
DOI's	https://doi.org/10.1038/s41590-023-01665-0
Status	E-pub ahead of print - 27 nov. 2023

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Hernández-López, P., van Diest, E., Brazda, P., Heijhuurs, S., Meringa, A., Hoorens van Heyningen, L., Riillo, C., Schwenzel, C., Zintchenko, M., Johanna, I., Nicolasen, M. J. T., Cleven, A., Kluiver, T. A., Millen, R., Zheng, J., Karaiskaki, F., Straetemans, T., Clevers, H., de Bree, R., ... Kuball, J. (2023). Dual targeting of cancer metabolome and stress antigens affects transcriptomic heterogeneity and efficacy of engineered T cells. Nature Immunology. Online publicatie vooraf. https://doi.org/10.1038/s41590-023-01665-0

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title = "Dual targeting of cancer metabolome and stress antigens affects transcriptomic heterogeneity and efficacy of engineered T cells",

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.",

author = "Patricia Hern{\'a}ndez-L{\'o}pez and {van Diest}, Eline and Peter Brazda and Sabine Heijhuurs and Angelo Meringa and {Hoorens van Heyningen}, Lauren and Caterina Riillo and Caroline Schwenzel and Marina Zintchenko and Inez Johanna and Nicolasen, {Mara J T} and Astrid Cleven and Kluiver, {Thomas A} and Rosemary Millen and Jiali Zheng and Froso Karaiskaki and Trudy Straetemans and Hans Clevers and {de Bree}, Remco and Stunnenberg, {Hendrik G} and Peng, {Weng Chuan} and Jeanine Roodhart and Susana Minguet and Zsolt Sebesty{\'e}n and Beringer, {Dennis X} and J{\"u}rgen Kuball",

note = "{\textcopyright} 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2023",

month = nov,

day = "27",

doi = "10.1038/s41590-023-01665-0",

language = "English",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

}

Hernández-López, P, van Diest, E, Brazda, P, Heijhuurs, S, Meringa, A, Hoorens van Heyningen, L, Riillo, C, Schwenzel, C, Zintchenko, M, Johanna, I, Nicolasen, MJT, Cleven, A, Kluiver, TA, Millen, R, Zheng, J, Karaiskaki, F, Straetemans, T, Clevers, H, de Bree, R, Stunnenberg, HG, Peng, WC, Roodhart, J, Minguet, S, Sebestyén, Z, Beringer, DX & Kuball, J 2023, 'Dual targeting of cancer metabolome and stress antigens affects transcriptomic heterogeneity and efficacy of engineered T cells', Nature Immunology. https://doi.org/10.1038/s41590-023-01665-0

TY - JOUR

T1 - Dual targeting of cancer metabolome and stress antigens affects transcriptomic heterogeneity and efficacy of engineered T cells

AU - Hernández-López, Patricia

AU - van Diest, Eline

AU - Brazda, Peter

AU - Heijhuurs, Sabine

AU - Meringa, Angelo

AU - Hoorens van Heyningen, Lauren

AU - Riillo, Caterina

AU - Schwenzel, Caroline

AU - Zintchenko, Marina

AU - Johanna, Inez

AU - Nicolasen, Mara J T

AU - Cleven, Astrid

AU - Kluiver, Thomas A

AU - Millen, Rosemary

AU - Zheng, Jiali

AU - Karaiskaki, Froso

AU - Straetemans, Trudy

AU - Clevers, Hans

AU - de Bree, Remco

AU - Stunnenberg, Hendrik G

AU - Peng, Weng Chuan

AU - Roodhart, Jeanine

AU - Minguet, Susana

AU - Sebestyén, Zsolt

AU - Beringer, Dennis X

AU - Kuball, Jürgen

PY - 2023/11/27

Y1 - 2023/11/27

N2 - 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.

AB - 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.

U2 - 10.1038/s41590-023-01665-0

DO - 10.1038/s41590-023-01665-0

M3 - Article

C2 - 38012415

SN - 1529-2908

JO - Nature Immunology

JF - Nature Immunology

ER -

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

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