Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and solid tumor microenvironment
© 2023. Springer Nature Limited..
The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumors is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquire early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogram and reverse the immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells of healthy donors or metastatic female breast cancer patients, induce robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a promising therapy for solid tumors.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
Nature communications - 14(2023), 1 vom: 15. Sept., Seite 5727 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Yufeng [VerfasserIn] |
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| Links: |
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| Themen: |
Immunosuppressive Agents |
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| Anmerkungen: |
Date Completed 18.09.2023 Date Revised 12.02.2024 published: Electronic UpdateOf: Res Sq. 2023 Feb 21;:. - PMID 36865255 Citation Status MEDLINE |
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| doi: |
10.1038/s41467-023-41282-x |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Stressed target cancer cells drive nongenetic reprogramming of CAR T cells and solid tumor microenvironment |
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| 520 | |a The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumors is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquire early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogram and reverse the immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells of healthy donors or metastatic female breast cancer patients, induce robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a promising therapy for solid tumors | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
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| 700 | 1 | |a Drum, David L |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Ruochuan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yida |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Fengfei |e verfasserin |4 aut | |
| 700 | 1 | |a Dal, Emre |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Jia, Jingyu |e verfasserin |4 aut | |
| 700 | 1 | |a Arya, Shahrzad |e verfasserin |4 aut | |
| 700 | 1 | |a Jia, Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Fan, Song |e verfasserin |4 aut | |
| 700 | 1 | |a Isakoff, Steven J |e verfasserin |4 aut | |
| 700 | 1 | |a Kehlmann, Allison M |e verfasserin |4 aut | |
| 700 | 1 | |a Dotti, Gianpietro |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Fubao |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Ferrone, Cristina R |e verfasserin |4 aut | |
| 700 | 1 | |a Taghian, Alphonse G |e verfasserin |4 aut | |
| 700 | 1 | |a DeLeo, Albert B |e verfasserin |4 aut | |
| 700 | 1 | |a Ventin, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Cattaneo, Giulia |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yongxiang |e verfasserin |4 aut | |
| 700 | 1 | |a Jounaidi, Youssef |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Peigen |e verfasserin |4 aut | |
| 700 | 1 | |a Maccalli, Cristina |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Hanyu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Cheng |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jibing |e verfasserin |4 aut | |
| 700 | 1 | |a Boland, Genevieve M |e verfasserin |4 aut | |
| 700 | 1 | |a Sadreyev, Ruslan I |e verfasserin |4 aut | |
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| 700 | 1 | |a Ferrone, Soldano |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xinhui |e verfasserin |4 aut | |
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