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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1101769/full |
| _version_ | 1797943901929078784 |
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| author | Kai Zhao Kai Zhao Kai Zhao Chunxiao Ren Donghai Tang Li Zhao Xianxian Chen Ying Wang Kailin Xu Kailin Xu Kailin Xu |
| author_facet | Kai Zhao Kai Zhao Kai Zhao Chunxiao Ren Donghai Tang Li Zhao Xianxian Chen Ying Wang Kailin Xu Kailin Xu Kailin Xu |
| author_sort | Kai Zhao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T20:31:27Z |
| format | Article |
| id | doaj.art-1ee4ba4712624746b2874d1e07997549 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-10T20:31:27Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-1ee4ba4712624746b2874d1e079975492023-01-25T05:41:40ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-01-011410.3389/fimmu.2023.11017691101769The altering cellular components and function in tumor microenvironment during remissive and relapsed stages of anti-CD19 CAR T-cell treated lymphoma miceKai Zhao0Kai Zhao1Kai Zhao2Chunxiao Ren3Donghai Tang4Li Zhao5Xianxian Chen6Ying Wang7Kailin Xu8Kailin Xu9Kailin Xu10Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaThe Key Lab of Bone Marrow Transplantation, Xuzhou, Jiangsu, ChinaBlood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaBlood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaBlood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaBlood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaBlood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, ChinaThe Key Lab of Bone Marrow Transplantation, Xuzhou, Jiangsu, ChinaAnti-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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1101769/fullchimeric antigen receptor T cellCD19tumor microenvironmentlymphomaimmunosuppression |
| spellingShingle | Kai Zhao Kai Zhao Kai Zhao Chunxiao Ren Donghai Tang Li Zhao Xianxian Chen Ying Wang Kailin Xu Kailin Xu Kailin Xu The altering cellular components and function in tumor microenvironment during remissive and relapsed stages of anti-CD19 CAR T-cell treated lymphoma mice Frontiers in Immunology chimeric antigen receptor T cell CD19 tumor microenvironment lymphoma immunosuppression |
| title | The altering cellular components and function in tumor microenvironment during remissive and relapsed stages of anti-CD19 CAR T-cell treated lymphoma mice |
| title_full | The altering cellular components and function in tumor microenvironment during remissive and relapsed stages of anti-CD19 CAR T-cell treated lymphoma mice |
| title_fullStr | The altering cellular components and function in tumor microenvironment during remissive and relapsed stages of anti-CD19 CAR T-cell treated lymphoma mice |
| title_full_unstemmed | The altering cellular components and function in tumor microenvironment during remissive and relapsed stages of anti-CD19 CAR T-cell treated lymphoma mice |
| title_short | The altering cellular components and function in tumor microenvironment during remissive and relapsed stages of anti-CD19 CAR T-cell treated lymphoma mice |
| title_sort | altering cellular components and function in tumor microenvironment during remissive and relapsed stages of anti cd19 car t cell treated lymphoma mice |
| topic | chimeric antigen receptor T cell CD19 tumor microenvironment lymphoma immunosuppression |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1101769/full |
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