PD-L1 CAR effector cells induce self-amplifying cytotoxic effects against target cells.

Autor:	Bajor M; Department of Clinical Immunology, Medical University of Warsaw, Warszawa, Mazowieckie, Poland.; Laboratory of Immunology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland., Graczyk-Jarzynka A; Laboratory of Immunology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.; Department of Immunology, Medical University of Warsaw, Warszawa, Poland., Marhelava K; Department of Clinical Immunology, Medical University of Warsaw, Warszawa, Mazowieckie, Poland.; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.; Laboratory for Cellular and Genetic Therapies, Medical University of Warsaw, Warsaw, Poland., Burdzinska A; Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warszawa, Poland., Muchowicz A; Department of Immunology, Medical University of Warsaw, Warszawa, Poland., Goral A; Department of Immunology, Medical University of Warsaw, Warszawa, Poland., Zhylko A; Department of Immunology, Medical University of Warsaw, Warszawa, Poland.; Doctoral School, Medical University of Warsaw, Warsaw, Poland., Soroczynska K; Department of Immunology, Medical University of Warsaw, Warszawa, Poland., Retecki K; Department of Immunology, Medical University of Warsaw, Warszawa, Poland., Krawczyk M; Laboratory of Immunology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.; Department of Immunology, Medical University of Warsaw, Warszawa, Poland.; Laboratory for Cellular and Genetic Therapies, Medical University of Warsaw, Warsaw, Poland.; Doctoral School of Translational Medicine, Centre of Postgraduate Medical Education, Warsaw, Poland., Klopotowska M; Department of Clinical Immunology, Medical University of Warsaw, Warszawa, Mazowieckie, Poland.; Laboratory of Immunology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland., Pilch Z; Department of Immunology, Medical University of Warsaw, Warszawa, Poland., Paczek L; Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warszawa, Poland.; Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland., Malmberg KJ; Department of Cancer Immunology, Radiumhospitalet, Oslo, Norway., Wälchli S; Department of Cellular Therapy, Oslo University Hospital, Oslo, Norway., Winiarska M; Department of Immunology, Medical University of Warsaw, Warszawa, Poland mwiniarska@wum.edu.pl radoslaw.zagozdzon@wum.edu.pl., Zagozdzon R; Department of Clinical Immunology, Medical University of Warsaw, Warszawa, Mazowieckie, Poland mwiniarska@wum.edu.pl radoslaw.zagozdzon@wum.edu.pl.; Laboratory for Cellular and Genetic Therapies, Medical University of Warsaw, Warsaw, Poland.; Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.; Department of Regenerative Medicine, The Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Jan; Vol. 10 (1).
DOI:	10.1136/jitc-2021-002500
Abstrakt:	Background: Immune checkpoint inhibitors and chimeric antigen receptor (CAR)-based therapies have transformed cancer treatment. Recently, combining these approaches into a strategy of PD-L1-targeted CAR has been proposed to target PD-L1 high tumors. Our study provides new information on the efficacy of such an approach against PD-L1 low targets. Methods: New atezolizumab-based PD-L1-targeted CAR was generated and introduced into T, NK, or NK-92 cells. Breast cancer MDA-MB-231 and MCF-7 cell lines or non-malignant cells (HEK293T, HMEC, MCF-10A, or BM-MSC) were used as targets to assess the reactivity or cytotoxic activity of the PD-L1-CAR-bearing immune effector cells. Stimulation with IFNγ or with supernatants from activated CAR T cells were used to induce upregulation of PD-L1 molecule expression on the target cells. HER2-CAR T cells were used for combination with PD-L1-CAR T cells against MCF-7 cells. Results: PD-L1-CAR effector cells responded vigorously with degranulation and cytokine production to PD-L1 high MDA-MB-231 cells, but not to PD-L1 low MCF-7 cells. However, in long-term killing assays, both MDA-MB-231 and MCF-7 cells were eliminated by the PD-L1-CAR cells, although with a delay in the case of PD-L1 low MCF-7 cells. Notably, the coculture of MCF-7 cells with activated PD-L1-CAR cells led to bystander induction of PD-L1 expression on MCF-7 cells and to the unique self-amplifying effect of the PD-L1-CAR cells. Accordingly, PD-L1-CAR T cells were active not only against MDA-MD-231 and MCF-7-PD-L1 but also against MCF-7-pLVX cells in tumor xenograft models. Importantly, we have also observed potent cytotoxic effects of PD-L1-CAR cells against non-malignant MCF-10A, HMEC, and BM-MSC cells, but not against HEK293T cells that initially did not express PD-L1 and were unresponsive to the stimulation . Finally, we have observed that HER-2-CAR T cells stimulate PD-L1 expression on MCF-7 cells and therefore accelerate the functionality of PD-L1-CAR T cells when used in combination. Conclusions: In summary, our studies show that CAR-effector cells trigger the expression of PD-L1 on target cells, which in case of PD-L1-CAR results in the unique self-amplification phenomenon. This self-amplifying effect could be responsible for the enhanced cytotoxicity of PD-L1-CAR T cells against both malignant and non-malignant cells and implies extensive caution in introducing PD-L1-CAR strategy into clinical studies. Competing Interests: Competing interests: K-JM is a consultant at Fate Therapeutics and a member of the SAB at Vycellix. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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