Abstract
Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.
| Original language | English |
|---|---|
| Pages (from-to) | 6081-6100.e26 |
| Journal | Cell |
| Volume | 184 |
| Issue number | 25 |
| DOIs | |
| State | Published - Dec 9 2021 |
Keywords
- CAR T cell
- ID3
- NK-like T cell
- SOX4
- T cell dysfunction
- T cell exhaustion
- cancer
- cell transfer therapy
- immunology
- immunotherapy
- pancreatic cancer
- single-cell RNA-seq
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An NK-like CAR T cell transition in CAR T cell dysfunction. / Good, Charly R.; Aznar, M. Angela; Kuramitsu, Shunichiro et al.
In: Cell, Vol. 184, No. 25, 09.12.2021, p. 6081-6100.e26.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - An NK-like CAR T cell transition in CAR T cell dysfunction
AU - Good, Charly R.
AU - Aznar, M. Angela
AU - Kuramitsu, Shunichiro
AU - Samareh, Parisa
AU - Agarwal, Sangya
AU - Donahue, Greg
AU - Ishiyama, Kenichi
AU - Wellhausen, Nils
AU - Rennels, Austin K.
AU - Ma, Yujie
AU - Tian, Lifeng
AU - Guedan, Sonia
AU - Alexander, Katherine A.
AU - Zhang, Zhen
AU - Rommel, Philipp C.
AU - Singh, Nathan
AU - Glastad, Karl M.
AU - Richardson, Max W.
AU - Watanabe, Keisuke
AU - Tanyi, Janos L.
AU - O'Hara, Mark H.
AU - Ruella, Marco
AU - Lacey, Simon F.
AU - Moon, Edmund K.
AU - Schuster, Stephen J.
AU - Albelda, Steven M.
AU - Lanier, Lewis L.
AU - Young, Regina M.
AU - Berger, Shelley L.
AU - June, Carl H.
N1 - Funding Information: Research supported by a SU2C-Lustgarten Foundation Translational Cancer Research Team Grant, grant numbers SU2-CAACR-DT21-17 and SU2C-RT6162. S.L.B. is supported by NIH grant CA078831. C.R.G. is supported by NIH grant CA232466 and the American Cancer Society – Rob Kugler – Postdoctoral Fellowship. R.M.Y. and C.H.J. are supported by NIH grant P01CA214278. C.H.J. and L.L.L. are supported by the Parker Institute for Cancer Immunotherapy. P.C.R. is supported by the National Institutes of Health/National Cancer Institute grant 5T32CA009140. We acknowledge the Parnassus Flow Cytometry Core, in part supported by the NIH DRC Center grants P30 DK063720 and S10 1S10OD018040-01, for use of the CyTOF instrument. The authors wish to thank E. John Wherry and Austin L. Good for their valuable feedback on this manuscript. C.R.G. M.A.A. and S.K. designed and conducted the experiments, interpreted the data, and wrote and prepared the manuscript. A.K.R. Y.M. L.T. S.A. S.G. N.W. M.W.R. N.S. P.C.R. and K.W. assisted with in vitro and in vivo assays. J.L.T. M.H.O. and S.J.S. provided clinical samples and expertise. S.M.A. and E.K.M. designed and performed the NY-ESO-1 models. M.R. assisted with supervision of in vitro experiments, and S.F.L. assisted with supervision of analyses of clinical samples. C.R.G. P.S. and G.D. performed bioinformatic analyses. K.A.A. K.M.G. and Z.Z. provided feedback on genomics experiments. K.I. designed and performed the mass cytometry assays. C.H.J. S.L.B. L.L.L. and R.M.Y. led the design, interpretation, and analysis of all experiments, and helped with the writing and preparation of the manuscript. R.M.Y. S.G. S.F.L. S.M.A. M.R. and C.H.J. are inventors on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and receive license revenue from such licenses. R.M.Y. is an inventor on patents and/or patent applications licensed to Tmunity Therapeutics and receives license revenue from such licenses. C.H.J. is a scientific founder of Tmunity Therapeutics and DeCART Therapeutics, and is a member of the scientific advisory boards of AC Immune, BluesphereBio, Cabaletta, Carisma, Cartography, Cellares, Celldex, Decheng, Poseida, Verismo, WIRB-Copernicus, and Ziopharm. S.J.S. is a consultant, on the scientific advisory board, and receives research support from Genentech/Roche, Novartis, and Juno Therapeutics. S.J.S. is a consultant for AlloGene, AstraZeneca, BeiGene, Regeneron, and Tesa Therapeutics. S.J.S. is a consultant and on the scientific advisory board for Loxo Oncology. S.J.S. is on the scientific advisory board for Nordic Nanovector. S.J.S. is a consultant and receives research support from Celgene. S.F.L. receives research funding from Tmunity Therapeutics and Cabaletta. M.R. is on the scientific advisory board of AbClon Inc. and consulted for BMS, nanoString, GSK, and Bayer. M.R. is the scientific founder of viTToria Biotherapeutics. L.L.L. is on the scientific advisory boards for Alector, Atreca, Dragonfly, DrenBio, Morphosys, Nkarta, Obsidian Therapeutics, Rubius, SBI, and Innovent. S.M.A. receives research funding from Tmunity Therapeutics, RAPT, and Incyte Corporation and is scientific advisor for Trizell, BioArdis, and Verismo. Funding Information: Research supported by a SU2C-Lustgarten Foundation Translational Cancer Research Team Grant, grant numbers SU2-CAACR-DT21-17 and SU2C-RT6162 . S.L.B. is supported by NIH grant CA078831 . C.R.G. is supported by NIH grant CA232466 and the American Cancer Society – Rob Kugler – Postdoctoral Fellowship. R.M.Y. and C.H.J. are supported by NIH grant P01CA214278 . C.H.J. and L.L.L. are supported by the Parker Institute for Cancer Immunotherapy . P.C.R. is supported by the National Institutes of Health/ National Cancer Institute grant 5T32CA009140 . We acknowledge the Parnassus Flow Cytometry Core, in part supported by the NIH DRC Center grants P30 DK063720 and S10 1S10OD018040-01 , for use of the CyTOF instrument. The authors wish to thank E. John Wherry and Austin L. Good for their valuable feedback on this manuscript. Funding Information: R.M.Y., S.G., S.F.L., S.M.A., M.R., and C.H.J. are inventors on patents and/or patent applications licensed to Novartis Institutes of Biomedical Research and receive license revenue from such licenses. R.M.Y. is an inventor on patents and/or patent applications licensed to Tmunity Therapeutics and receives license revenue from such licenses. C.H.J. is a scientific founder of Tmunity Therapeutics and DeCART Therapeutics, and is a member of the scientific advisory boards of AC Immune, BluesphereBio, Cabaletta, Carisma, Cartography, Cellares, Celldex, Decheng, Poseida, Verismo, WIRB-Copernicus, and Ziopharm. S.J.S. is a consultant, on the scientific advisory board, and receives research support from Genentech/Roche, Novartis, and Juno Therapeutics. S.J.S. is a consultant for AlloGene, AstraZeneca, BeiGene, Regeneron, and Tesa Therapeutics. S.J.S. is a consultant and on the scientific advisory board for Loxo Oncology. S.J.S. is on the scientific advisory board for Nordic Nanovector. S.J.S. is a consultant and receives research support from Celgene. S.F.L. receives research funding from Tmunity Therapeutics and Cabaletta. M.R. is on the scientific advisory board of AbClon Inc. and consulted for BMS, nanoString, GSK, and Bayer. M.R. is the scientific founder of viTToria Biotherapeutics. L.L.L. is on the scientific advisory boards for Alector, Atreca, Dragonfly, DrenBio, Morphosys, Nkarta, Obsidian Therapeutics, Rubius, SBI, and Innovent. S.M.A. receives research funding from Tmunity Therapeutics, RAPT, and Incyte Corporation and is scientific advisor for Trizell, BioArdis, and Verismo. Publisher Copyright: © 2021 Elsevier Inc.
PY - 2021/12/9
Y1 - 2021/12/9
N2 - Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.
AB - Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.
KW - CAR T cell
KW - ID3
KW - NK-like T cell
KW - SOX4
KW - T cell dysfunction
KW - T cell exhaustion
KW - cancer
KW - cell transfer therapy
KW - immunology
KW - immunotherapy
KW - pancreatic cancer
KW - single-cell RNA-seq
UR - http://www.scopus.com/inward/record.url?scp=85120635876&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2021.11.016
DO - 10.1016/j.cell.2021.11.016
M3 - Article
C2 - 34861191
AN - SCOPUS:85120635876
SN - 0092-8674
VL - 184
SP - 6081-6100.e26
JO - Cell
JF - Cell
IS - 25
ER -