CD47 expression is critical for CAR T-cell survival in vivo
Background CD47 is an attractive immunotherapeutic target because it is highly expressed on multiple solid tumors. However, CD47 is also expressed on T cells. Limited studies have evaluated CD47-chimeric antigen receptor (CAR) T cells, and the role of CD47 in CAR T-cell function remains largely unkn...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/3/e005857.full |
| _version_ | 1797870014725881856 |
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| author | Stephen Gottschalk Phuong Nguyen Christopher DeRenzo Giedre Krenciute Alex N Beckett Peter Chockley Shondra M Pruett-Miller Peter Vogel Heather Sheppard |
| author_facet | Stephen Gottschalk Phuong Nguyen Christopher DeRenzo Giedre Krenciute Alex N Beckett Peter Chockley Shondra M Pruett-Miller Peter Vogel Heather Sheppard |
| author_sort | Stephen Gottschalk |
| collection | DOAJ |
| description | Background CD47 is an attractive immunotherapeutic target because it is highly expressed on multiple solid tumors. However, CD47 is also expressed on T cells. Limited studies have evaluated CD47-chimeric antigen receptor (CAR) T cells, and the role of CD47 in CAR T-cell function remains largely unknown.Methods Here, we describe the development of CD47-CAR T cells derived from a high affinity signal regulatory protein α variant CV1, which binds CD47. CV1-CAR T cells were generated from human peripheral blood mononuclear cells and evaluated in vitro and in vivo. The role of CD47 in CAR T-cell function was examined by knocking out CD47 in T cells followed by downstream functional analyses.Results While CV1-CAR T cells are specific and exhibit potent activity in vitro they lacked antitumor activity in xenograft models. Mechanistic studies revealed CV1-CAR T cells downregulate CD47 to overcome fratricide, but CD47 loss resulted in their failure to expand and persist in vivo. This effect was not limited to CV1-CAR T cells, since CD47 knockout CAR T cells targeting another solid tumor antigen exhibited the same in vivo fate. Further, CD47 knockout T cells were sensitive to macrophage-mediated phagocytosis.Conclusions These findings highlight that CD47 expression is critical for CAR T-cell survival in vivo and is a ‘sine qua non’ for successful adoptive T-cell therapy. |
| first_indexed | 2024-04-10T00:21:43Z |
| format | Article |
| id | doaj.art-0dce8e42cb164bc3af9c4f217878a8e2 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-10T00:21:43Z |
| publishDate | 2023-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-0dce8e42cb164bc3af9c4f217878a8e22023-03-15T21:00:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-03-0111310.1136/jitc-2022-005857CD47 expression is critical for CAR T-cell survival in vivoStephen Gottschalk0Phuong Nguyen1Christopher DeRenzo2Giedre Krenciute3Alex N Beckett4Peter Chockley5Shondra M Pruett-Miller6Peter Vogel7Heather Sheppard8Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Bone Marrow Transplantation and Cellular Therapy, St Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Bone Marrow Transplantation and Cellular Therapy, St Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Bone Marrow Transplantation and Cellular Therapy, St Jude Children`s Research Hospital, Memphis, Tennessee, USAGraduate School of Biomedical Sciences, St Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Bone Marrow Transplantation and Cellular Therapy, St Jude Children`s Research Hospital, Memphis, Tennessee, USACenter for Advanced Genome Engineering, St Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Pathology, St Jude Children`s Research Hospital, Memphis, Tennessee, USADepartment of Pathology, St Jude Children`s Research Hospital, Memphis, Tennessee, USABackground CD47 is an attractive immunotherapeutic target because it is highly expressed on multiple solid tumors. However, CD47 is also expressed on T cells. Limited studies have evaluated CD47-chimeric antigen receptor (CAR) T cells, and the role of CD47 in CAR T-cell function remains largely unknown.Methods Here, we describe the development of CD47-CAR T cells derived from a high affinity signal regulatory protein α variant CV1, which binds CD47. CV1-CAR T cells were generated from human peripheral blood mononuclear cells and evaluated in vitro and in vivo. The role of CD47 in CAR T-cell function was examined by knocking out CD47 in T cells followed by downstream functional analyses.Results While CV1-CAR T cells are specific and exhibit potent activity in vitro they lacked antitumor activity in xenograft models. Mechanistic studies revealed CV1-CAR T cells downregulate CD47 to overcome fratricide, but CD47 loss resulted in their failure to expand and persist in vivo. This effect was not limited to CV1-CAR T cells, since CD47 knockout CAR T cells targeting another solid tumor antigen exhibited the same in vivo fate. Further, CD47 knockout T cells were sensitive to macrophage-mediated phagocytosis.Conclusions These findings highlight that CD47 expression is critical for CAR T-cell survival in vivo and is a ‘sine qua non’ for successful adoptive T-cell therapy.https://jitc.bmj.com/content/11/3/e005857.full |
| spellingShingle | Stephen Gottschalk Phuong Nguyen Christopher DeRenzo Giedre Krenciute Alex N Beckett Peter Chockley Shondra M Pruett-Miller Peter Vogel Heather Sheppard CD47 expression is critical for CAR T-cell survival in vivo Journal for ImmunoTherapy of Cancer |
| title | CD47 expression is critical for CAR T-cell survival in vivo |
| title_full | CD47 expression is critical for CAR T-cell survival in vivo |
| title_fullStr | CD47 expression is critical for CAR T-cell survival in vivo |
| title_full_unstemmed | CD47 expression is critical for CAR T-cell survival in vivo |
| title_short | CD47 expression is critical for CAR T-cell survival in vivo |
| title_sort | cd47 expression is critical for car t cell survival in vivo |
| url | https://jitc.bmj.com/content/11/3/e005857.full |
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