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Programmed death-ligand 1 expression on CD22-specific chimeric antigen receptor-modified T cells weakens antitumor potential.

ABSTRACT: The molecules of programmed cell death protein-1 (PD-1) and ligand-1 (PD-L1) become new therapeutic targets for cancer therapy. Although tumor-expressed PD-L1 molecule is frequently dispensable for checkpoint blockade in some cancer patients, recent studies suggest that T cell-expressed PD-L1 molecule might play a crucial role in antitumor immunity. Here, to investigate CD22 chimeric antigen receptor (CAR)-T cell therapy, we have generated the different CD22 CAR-T constructs. We noticed that tumor cells induced PD-L1 expression on the surface of CD22 CAR-T cells. The induced PD-L1 might limit immunogenic responses of CAR-T cells. T cell-expressed PD-L1 leads to a suppressive signal by PD-1/PD-L1 engagement of CD22 CAR-T cells. Meanwhile, PD-L1 suppresses CD22 CAR-T cell differentiation into memory T cells and negatively affected secretions of several essential cytokines, such as interleukin-2 (IL-2) and tumor necrosis factor (TNF)-α. We further observed that anti-PD-L1 monoclonal antibodies rescued cytokine secretion of CD22 CAR-T cells rather than anti-PD-1 monoclonal antibodies. Our current studies provide a potential mechanism to understand the functions and roles of T cell-expressed PD-L1 in tumor microenvironment. These results will encourage the physicians to re-recognize the important roles of PD-L1 in cancer immunotherapy studies and provide the helpful guidance for clinical operation of PD-L1 inhibition drugs.

SUBMITTER: Liu J

PROVIDER: S-EPMC9149589 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Programmed death-ligand 1 expression on CD22-specific chimeric antigen receptor-modified T cells weakens antitumor potential.

Liu Jie J Zhang Fengjuan F Yu Jian J Zhao Qi Q

MedComm 20220529 2

The molecules of programmed cell death protein-1 (PD-1) and ligand-1 (PD-L1) become new therapeutic targets for cancer therapy. Although tumor-expressed PD-L1 molecule is frequently dispensable for checkpoint blockade in some cancer patients, recent studies suggest that T cell-expressed PD-L1 molecule might play a crucial role in antitumor immunity. Here, to investigate CD22 chimeric antigen receptor (CAR)-T cell therapy, we have generated the different CD22 CAR-T constructs. We noticed that tum ...[more]

PMID: 35665369

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Project description:Tumor immunotherapy based on the use of chimeric antigen receptor modified T cells (CAR T cells) is a promising approach for the treatment of refractory hematological malignancies. However, a robust response mediated by CAR T cells is observed only in a minority of patients and the expansion and persistence of CAR T cells in vivo is mostly unpredictable.Lenalidomide (LEN) is an immunomodulatory drug currently approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma, while it is clinically tested in the therapy of diffuse large B-cell lymphoma of activated B cell immunophenotype. LEN was shown to increase antitumor immune responses at least partially by modulating the activity of E3 ubiquitin ligase Cereblon, which leads to increased ubiquitinylation of Ikaros and Aiolos transcription factors, which in turn results in changed expression of various receptors on the surface of tumor cells. In order to enhance the effectiveness of CAR-based immunotherapy, we assessed the anti-lymphoma efficacy of LEN in combination with CAR19 T cells or CAR20 T cells in vitro and in vivo using various murine models of aggressive B-cell non-Hodgkin lymphomas (B-NHL).Immunodeficient NSG mice were transplanted with various human B-NHL cells followed by treatment with CAR19 or CAR20 T cells with or without LEN. Next, CAR19 T cells were subjected to series of tests in vitro to evaluate their response and signaling capacity following recognition of B cell in the presence or absence of LEN.Our data shows that LEN significantly enhances antitumor functions of CAR19 and CAR20 T cells in vivo. Additionally, it enhances production of interferon gamma by CAR19 T cells and augments cell signaling via CAR19 protein in T cells in vitro. Our data further suggests that LEN works through direct effects on T cells but not on B-NHL cells. The biochemical events underlying this costimulatory effect of LEN are currently being investigated. In summary, our data supports the use of LEN for augmentation of CAR-based immunotherapy in the clinical grounds.

Dataset Information

Programmed death-ligand 1 expression on CD22-specific chimeric antigen receptor-modified T cells weakens antitumor potential.

Publications

Programmed death-ligand 1 expression on CD22-specific chimeric antigen receptor-modified T cells weakens antitumor potential.

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