Trogocytosis and fratricide killing impede MSLN-directed CAR T cell functionality

Schoutrop, Esther; Renken, Stefanie; Nilsson, Isabella Micallef; Hahn, Paula; Poiret, Thomas; Kiessling, Rolf; Wickström, Stina L.; Mattsson, Jonas; Magalhaes, Isabelle

doi:10.1080/2162402x.2022.2093426

Cited by 16 publications

(22 citation statements)

References 44 publications

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“… 27 45 In line with previous data, trogocytic CAR T cells displayed a T EM profile with higher expression levels of PD-1, LAG-3 and TIM-3, as well as CD56 and FASL, indicative of both activation and exhaustion. 45 46 The low frequency of trogocytic M1xx CAR T cells observed in our two models suggest that superior tumor control as seen with M1xx CAR T cells correlates to lower trogocytic activity.…”

Section: Discussionmentioning

confidence: 70%

Tuned activation of MSLN-CAR T cells induces superior antitumor responses in ovarian cancer models

Schoutrop

Poiret

El-Serafi

et al. 2023

J Immunother Cancer

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BackgroundLimited persistence of functional CAR T cells in the immunosuppressive solid tumor microenvironment remains a major hurdle in the successful translation of CAR T cell therapy to treat solid tumors. Fine-tuning of CAR T cell activation by mutating CD3ζ chain immunoreceptor tyrosine-based activation motifs (ITAMs) in CD19-CAR T cells (containing the CD28 costimulatory domain) has proven to extend functional CAR T cell persistence in preclinical models of B cell malignancies.MethodsIn this study, two conventional second-generation MSLN-CAR T cell constructs encoding for either a CD28 co-stimulatory (M28z) or 4-1BB costimulatory (MBBz) domain and a novel mesothelin (MSLN)-directed CAR T cell construct encoding for the CD28 costimulatory domain and CD3ζ chain containing a single ITAM (M1xx) were evaluated using in vitro and in vivo preclinical models of ovarian cancer. Two ovarian cancer cell lines and two orthotopic models of ovarian cancer in NSG mice were used: SKOV-3 cells inoculated through microsurgery in the ovary and to mimic a disseminated model of advanced ovarian cancer, OVCAR-4 cells injected intraperitoneally. MSLN-CAR T cell treatment efficacy was evaluated by survival analysis and the characterization and quantification of the different MSLN-CAR T cells were performed by flow cytometry, quantitative PCR and gene expression analysis.ResultsM1xx CAR T cells elicited superior antitumor potency and persistence, as compared with the conventional second generation M28z and MBBz CAR T cells. Ex vivo M28z and MBBz CAR T cells displayed a more exhausted phenotype than M1xx CAR T cells as determined by co-expression of PD-1, LAG-3 and TIM-3. Furthermore, M1xx CAR T cells showed superior ex vivo IFNy, TNF and GzB production and were characterized by a self-renewal gene signature.ConclusionsAltogether, our study demonstrates the enhanced therapeutic potential of MSLN-CAR T cells expressing a mutated CD3ζ chain containing a single ITAM for the treatment of ovarian cancer. CAR T cells armored with calibrated activation potential may improve the clinical responses in solid tumors.

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Section: Discussionmentioning

confidence: 70%

Tuned activation of MSLN-CAR T cells induces superior antitumor responses in ovarian cancer models

Schoutrop

Poiret

El-Serafi

et al. 2023

J Immunother Cancer

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“…Overexpression of MSLN can be detected in CRC ( 30 ). MSLN is an important CAR-T cells target in solid tumors ( 31 , 32 ). In a recent study, the efficacy of MSLN-CAR-T cells on colon cancer xenografts was investigated.…”

Section: Basic Experimental Of Car-t Cells Therapy For Crcmentioning

confidence: 99%

Recent advances in CAR-T cells therapy for colorectal cancer

Qin

Chen

et al. 2022

Front. Immunol.

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Colorectal cancer (CRC) is the third most common cancer, with a high mortality rate and a serious impact on people’s life and health. In recent years, adoptive chimeric antigen receptor T (CAR-T) cells therapy has shown well efficacy in the treatment of hematological malignancies, but there are still many problems and challenges in solid tumors such as CRC. For example, the tumor immunosuppressive microenvironment, the low targeting of CAR-T cells, the short time of CAR-T cells in vivo, and the limited proliferation capacity of CAR-T cells, CAR-T cells can not effectively infiltrate into the tumor and so on. New approaches have been proposed to address these challenges in CRC, and this review provides a comprehensive overview of the current state of CAR-T cells therapy in CRC.

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“…Trogocytosis is a rapid process of cellular interaction that occurs in immunotherapy [ 17 , 18 ]. Immune cells, including T cells and natural killer (NK) cells, physically nibble off a portion of the tumor cell membrane at the stage of identifying the tumor cell, transferring antigens from the cell membrane of the target cell to the surface of the immune cell [ 19 , 20 ]. After the antigen is transferred to immune cells that do not express the antigen themselves, it can lead to mutual killing of immune cells, inhibit the effectiveness of immunotherapy, and promote tumor growth and metastasis [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Photo-Driven In Situ Solidification of Whole Cells through Inhibition of Trogocytosis for Immunotherapy

Liu,

Huang,

Zhang

et al. 2024

Research

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Achieving antitumor immunotherapy based on hybridization of multiple types of inactivated cells has attracted a lot of attention. However, the hybridized cells of disordered structure could result in the shedding of antigens and their transfer to immune cells, which suppresses tumor immunity through trogocytosis. Here, we report a strategy for in situ solidification of tumor whole cell by biomineralization for sustained stimulation of antitumor immunity. The near-infrared light was used to accelerate the breaking of Au=P bonds in auranofin, and the exposed Au atoms biomineralize at the secondary structure (β-corner) of the protein to form Au nanocrystals with in situ protein coronas in tumor cells. Au nanocrystals are anchored to the tumor cells through protein coronas, which fixes the morphology and antigens of whole tumor cells, rendering them physiologically inactive. Interestingly, this solidified tumor cell prevents immune cells from undergoing trogocytosis, which inhibits proximal and distal tumor growth. Thus, this study presents the strategy of solidified cells and its potential application in tumor immunotherapy.

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Trogocytosis and fratricide killing impede MSLN-directed CAR T cell functionality

Cited by 16 publications

References 44 publications

Tuned activation of MSLN-CAR T cells induces superior antitumor responses in ovarian cancer models

Tuned activation of MSLN-CAR T cells induces superior antitumor responses in ovarian cancer models

Recent advances in CAR-T cells therapy for colorectal cancer

Photo-Driven In Situ Solidification of Whole Cells through Inhibition of Trogocytosis for Immunotherapy

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