The altering cellular components and function in tumor microenvironment during remissive and relapsed stages of anti-CD19 CAR T-cell treated lymphoma mice
Anti-CD19 chimeric antigen receptor (CAR) T cells represent a highly promising strategy for B-cell malignancies. Despite the inspiring initial achievement, remission in a notable fraction of subjects is short-lived, and relapse remains a major challenge. Tumor microenvironment (TME) was proved to be...
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| Published in: | Frontiers in immunology Vol. 14; p. 1101769 |
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| Main Authors: | , , , , , , |
| Format: | Journal Article |
| Language: | English |
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25.01.2023
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| Abstract | Anti-CD19 chimeric antigen receptor (CAR) T cells represent a highly promising strategy for B-cell malignancies. Despite the inspiring initial achievement, remission in a notable fraction of subjects is short-lived, and relapse remains a major challenge. Tumor microenvironment (TME) was proved to be aroused by CAR T cells; however, little is known about the dynamic characteristics of cellular components in TME especially during the different phases of disease after anti-CD19 CAR T-cell treatment. We took advantage of an immunocompetent model receiving syngeneic A20 lymphoma cells to dissect the changes in TME with or without CAR T-cell injection. We found that anti-CD19 CAR T-cell treatment attenuated the symptoms of lymphoma and significantly prolonged mice survival through eradicating systemic CD19
+
cells. Increased myeloid subsets, including CD11c
+
DCs and F4/80
+
macrophages with higher MHC II and CD80 expression in bone marrow, spleen, and liver, were detected when mice reached remission after anti-CD19 CAR T treatment. Compared to mice without anti-CD19 CAR T administration, intrinsic T cells were triggered to produce more IFN-γ and TNF-α. However, some lymphoma mice relapsed by day 42 after therapy, which coincided with CAR T-cell recession, decreased myeloid cell activation and increased Treg cells. Elevated intrinsic T cells with high PD-1 and TIGIT exhaust signatures and attenuated cytotoxicity in TME were associated with the late-stage relapse of CAR T-cell treatment. In summary, the cellular compositions of TME as allies of CAR T cells may contribute to the anti-tumor efficacy at the initial stage, whereas anti-CD19 CAR T-cell disappearance and host response immunosuppression may work together to cause lymphoma relapse after an initial, near-complete elimination phase. |
|---|---|
| AbstractList | Anti-CD19 chimeric antigen receptor (CAR) T cells represent a highly promising strategy for B-cell malignancies. Despite the inspiring initial achievement, remission in a notable fraction of subjects is short-lived, and relapse remains a major challenge. Tumor microenvironment (TME) was proved to be aroused by CAR T cells; however, little is known about the dynamic characteristics of cellular components in TME especially during the different phases of disease after anti-CD19 CAR T-cell treatment. We took advantage of an immunocompetent model receiving syngeneic A20 lymphoma cells to dissect the changes in TME with or without CAR T-cell injection. We found that anti-CD19 CAR T-cell treatment attenuated the symptoms of lymphoma and significantly prolonged mice survival through eradicating systemic CD19+ cells. Increased myeloid subsets, including CD11c+ DCs and F4/80+ macrophages with higher MHC II and CD80 expression in bone marrow, spleen, and liver, were detected when mice reached remission after anti-CD19 CAR T treatment. Compared to mice without anti-CD19 CAR T administration, intrinsic T cells were triggered to produce more IFN-γ and TNF-α. However, some lymphoma mice relapsed by day 42 after therapy, which coincided with CAR T-cell recession, decreased myeloid cell activation and increased Treg cells. Elevated intrinsic T cells with high PD-1 and TIGIT exhaust signatures and attenuated cytotoxicity in TME were associated with the late-stage relapse of CAR T-cell treatment. In summary, the cellular compositions of TME as allies of CAR T cells may contribute to the anti-tumor efficacy at the initial stage, whereas anti-CD19 CAR T-cell disappearance and host response immunosuppression may work together to cause lymphoma relapse after an initial, near-complete elimination phase. Anti-CD19 chimeric antigen receptor (CAR) T cells represent a highly promising strategy for B-cell malignancies. Despite the inspiring initial achievement, remission in a notable fraction of subjects is short-lived, and relapse remains a major challenge. Tumor microenvironment (TME) was proved to be aroused by CAR T cells; however, little is known about the dynamic characteristics of cellular components in TME especially during the different phases of disease after anti-CD19 CAR T-cell treatment. We took advantage of an immunocompetent model receiving syngeneic A20 lymphoma cells to dissect the changes in TME with or without CAR T-cell injection. We found that anti-CD19 CAR T-cell treatment attenuated the symptoms of lymphoma and significantly prolonged mice survival through eradicating systemic CD19+ cells. Increased myeloid subsets, including CD11c+ DCs and F4/80+ macrophages with higher MHC II and CD80 expression in bone marrow, spleen, and liver, were detected when mice reached remission after anti-CD19 CAR T treatment. Compared to mice without anti-CD19 CAR T administration, intrinsic T cells were triggered to produce more IFN-γ and TNF-α. However, some lymphoma mice relapsed by day 42 after therapy, which coincided with CAR T-cell recession, decreased myeloid cell activation and increased Treg cells. Elevated intrinsic T cells with high PD-1 and TIGIT exhaust signatures and attenuated cytotoxicity in TME were associated with the late-stage relapse of CAR T-cell treatment. In summary, the cellular compositions of TME as allies of CAR T cells may contribute to the anti-tumor efficacy at the initial stage, whereas anti-CD19 CAR T-cell disappearance and host response immunosuppression may work together to cause lymphoma relapse after an initial, near-complete elimination phase.Anti-CD19 chimeric antigen receptor (CAR) T cells represent a highly promising strategy for B-cell malignancies. Despite the inspiring initial achievement, remission in a notable fraction of subjects is short-lived, and relapse remains a major challenge. Tumor microenvironment (TME) was proved to be aroused by CAR T cells; however, little is known about the dynamic characteristics of cellular components in TME especially during the different phases of disease after anti-CD19 CAR T-cell treatment. We took advantage of an immunocompetent model receiving syngeneic A20 lymphoma cells to dissect the changes in TME with or without CAR T-cell injection. We found that anti-CD19 CAR T-cell treatment attenuated the symptoms of lymphoma and significantly prolonged mice survival through eradicating systemic CD19+ cells. Increased myeloid subsets, including CD11c+ DCs and F4/80+ macrophages with higher MHC II and CD80 expression in bone marrow, spleen, and liver, were detected when mice reached remission after anti-CD19 CAR T treatment. Compared to mice without anti-CD19 CAR T administration, intrinsic T cells were triggered to produce more IFN-γ and TNF-α. However, some lymphoma mice relapsed by day 42 after therapy, which coincided with CAR T-cell recession, decreased myeloid cell activation and increased Treg cells. Elevated intrinsic T cells with high PD-1 and TIGIT exhaust signatures and attenuated cytotoxicity in TME were associated with the late-stage relapse of CAR T-cell treatment. In summary, the cellular compositions of TME as allies of CAR T cells may contribute to the anti-tumor efficacy at the initial stage, whereas anti-CD19 CAR T-cell disappearance and host response immunosuppression may work together to cause lymphoma relapse after an initial, near-complete elimination phase. Anti-CD19 chimeric antigen receptor (CAR) T cells represent a highly promising strategy for B-cell malignancies. Despite the inspiring initial achievement, remission in a notable fraction of subjects is short-lived, and relapse remains a major challenge. Tumor microenvironment (TME) was proved to be aroused by CAR T cells; however, little is known about the dynamic characteristics of cellular components in TME especially during the different phases of disease after anti-CD19 CAR T-cell treatment. We took advantage of an immunocompetent model receiving syngeneic A20 lymphoma cells to dissect the changes in TME with or without CAR T-cell injection. We found that anti-CD19 CAR T-cell treatment attenuated the symptoms of lymphoma and significantly prolonged mice survival through eradicating systemic CD19 + cells. Increased myeloid subsets, including CD11c + DCs and F4/80 + macrophages with higher MHC II and CD80 expression in bone marrow, spleen, and liver, were detected when mice reached remission after anti-CD19 CAR T treatment. Compared to mice without anti-CD19 CAR T administration, intrinsic T cells were triggered to produce more IFN-γ and TNF-α. However, some lymphoma mice relapsed by day 42 after therapy, which coincided with CAR T-cell recession, decreased myeloid cell activation and increased Treg cells. Elevated intrinsic T cells with high PD-1 and TIGIT exhaust signatures and attenuated cytotoxicity in TME were associated with the late-stage relapse of CAR T-cell treatment. In summary, the cellular compositions of TME as allies of CAR T cells may contribute to the anti-tumor efficacy at the initial stage, whereas anti-CD19 CAR T-cell disappearance and host response immunosuppression may work together to cause lymphoma relapse after an initial, near-complete elimination phase. Anti-CD19 chimeric antigen receptor (CAR) T cells represent a highly promising strategy for B-cell malignancies. Despite the inspiring initial achievement, remission in a notable fraction of subjects is short-lived, and relapse remains a major challenge. Tumor microenvironment (TME) was proved to be aroused by CAR T cells; however, little is known about the dynamic characteristics of cellular components in TME especially during the different phases of disease after anti-CD19 CAR T-cell treatment. We took advantage of an immunocompetent model receiving syngeneic A20 lymphoma cells to dissect the changes in TME with or without CAR T-cell injection. We found that anti-CD19 CAR T-cell treatment attenuated the symptoms of lymphoma and significantly prolonged mice survival through eradicating systemic CD19 cells. Increased myeloid subsets, including CD11c DCs and F4/80 macrophages with higher MHC II and CD80 expression in bone marrow, spleen, and liver, were detected when mice reached remission after anti-CD19 CAR T treatment. Compared to mice without anti-CD19 CAR T administration, intrinsic T cells were triggered to produce more IFN-γ and TNF-α. However, some lymphoma mice relapsed by day 42 after therapy, which coincided with CAR T-cell recession, decreased myeloid cell activation and increased Treg cells. Elevated intrinsic T cells with high PD-1 and TIGIT exhaust signatures and attenuated cytotoxicity in TME were associated with the late-stage relapse of CAR T-cell treatment. In summary, the cellular compositions of TME as allies of CAR T cells may contribute to the anti-tumor efficacy at the initial stage, whereas anti-CD19 CAR T-cell disappearance and host response immunosuppression may work together to cause lymphoma relapse after an initial, near-complete elimination phase. |
| Author | Tang, Donghai Zhao, Li Zhao, Kai Ren, Chunxiao Wang, Ying Xu, Kailin Chen, Xianxian |
| AuthorAffiliation | 1 Blood Diseases Institute, Xuzhou Medical University , Xuzhou, Jiangsu , China 3 The Key Lab of Bone Marrow Transplantation, Xuzhou , Jiangsu , China 2 Department of Hematology, The Affiliated Hospital of Xuzhou Medical University , Xuzhou, Jiangsu , China |
| AuthorAffiliation_xml | – name: 3 The Key Lab of Bone Marrow Transplantation, Xuzhou , Jiangsu , China – name: 1 Blood Diseases Institute, Xuzhou Medical University , Xuzhou, Jiangsu , China – name: 2 Department of Hematology, The Affiliated Hospital of Xuzhou Medical University , Xuzhou, Jiangsu , China |
| Author_xml | – sequence: 1 givenname: Kai surname: Zhao fullname: Zhao, Kai – sequence: 2 givenname: Chunxiao surname: Ren fullname: Ren, Chunxiao – sequence: 3 givenname: Donghai surname: Tang fullname: Tang, Donghai – sequence: 4 givenname: Li surname: Zhao fullname: Zhao, Li – sequence: 5 givenname: Xianxian surname: Chen fullname: Chen, Xianxian – sequence: 6 givenname: Ying surname: Wang fullname: Wang, Ying – sequence: 7 givenname: Kailin surname: Xu fullname: Xu, Kailin |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/36761733$$D View this record in MEDLINE/PubMed |
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| Cites_doi | 10.1038/s41467-021-20893-2 10.1182/blood.2020007445 10.1038/s41591-018-0010-1 10.1002/cam4.3259 10.1038/nm.3394 10.1056/NEJMoa1407222 10.1038/s41586-022-05140-y 10.1200/JCO.21.01676 10.1158/2159-8290.CD-20-1661 10.1111/ajt.16275 10.1016/j.ymthe.2021.02.024 10.1126/sciimmunol.abd4344 10.1038/s43018-020-0036-4 10.1056/NEJMoa1103849 10.3390/cells10112845 10.1111/cas.14069 10.1016/j.ejphar.2022.175229 10.1038/s41591-022-01916-x 10.3791/58492 10.1016/j.cell.2021.05.027 10.1038/nrd3683 10.1038/nri3862 10.1056/NEJMoa1709919 10.1126/sciadv.abj2820 10.1126/scitranslmed.aac5415 10.1002/ajh.25108 10.1038/s41577-019-0127-6 10.1002/ajh.26301 10.1038/nrclinonc.2016.217 10.1038/s43018-020-0038-2 10.1186/s13045-018-0629-x 10.1084/jem.20182375 10.1038/s41573-022-00520-5 10.1038/s41591-020-1061-7 |
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| Copyright | Copyright © 2023 Zhao, Ren, Tang, Zhao, Chen, Wang and Xu. Copyright © 2023 Zhao, Ren, Tang, Zhao, Chen, Wang and Xu 2023 Zhao, Ren, Tang, Zhao, Chen, Wang and Xu |
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| Keywords | immunosuppression chimeric antigen receptor T cell tumor microenvironment CD19 lymphoma |
| Language | English |
| License | Copyright © 2023 Zhao, Ren, Tang, Zhao, Chen, Wang and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by: Lujun Chen, First People’s Hospital of Changzhou, China These authors have contributed equally to this work Reviewed by: Ling Xu, Jinan University, China; Wei Luo, Purdue University Indianapolis, United States; Na Li, Ningbo University, China This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology |
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| Snippet | Anti-CD19 chimeric antigen receptor (CAR) T cells represent a highly promising strategy for B-cell malignancies. Despite the inspiring initial achievement,... |
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| SubjectTerms | Animals CD19 chimeric antigen receptor T cell Immunology immunosuppression Immunotherapy, Adoptive lymphoma Lymphoma - therapy Lymphoma, B-Cell Mice Neoplasm Recurrence, Local Receptors, Chimeric Antigen Tumor Microenvironment |
| Title | The altering cellular components and function in tumor microenvironment during remissive and relapsed stages of anti-CD19 CAR T-cell treated lymphoma mice |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/36761733 https://www.proquest.com/docview/2775617483 https://pubmed.ncbi.nlm.nih.gov/PMC9905118 https://doaj.org/article/1ee4ba4712624746b2874d1e07997549 |
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