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
Main Authors: Zhao, Kai, Ren, Chunxiao, Tang, Donghai, Zhao, Li, Chen, Xianxian, Wang, Ying, Xu, Kailin
Format: Journal Article
Language:English
Published: Switzerland Frontiers Media S.A 25.01.2023
Subjects:
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
immunosuppression
chimeric antigen receptor T cell
tumor microenvironment
CD19
lymphoma
ISSN:1664-3224, 1664-3224
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Summary: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.
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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
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2023.1101769