Universität zu Köln

Montesinos-Rongen, Manuel, Sanchez-Ruiz, Monica, Siebert, Susann, Winter, Claudia, Siebert, Reiner, Brunn, Anna and Deckert, Martina (2022). Expression of Cas9 in a Syngeneic Model of Primary Central Nervous System Lymphoma Induces Intracerebral NK and CD8 T Cell-Mediated Lymphoma Cell Lysis Via Perforin. CRISPR J., 5 (5). S. 726 - 740. NEW ROCHELLE: MARY ANN LIEBERT, INC. ISSN 2573-1602

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Abstract

The development of clustered regulatory interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR-Cas9)-mediated gene modification has opened an exciting avenue of targeting genes to study the pathogenesis of diseases and to develop novel therapeutic concepts. However, as the effector protein Cas9 is of bacterial origin, unwanted side effects due to a host immune response against Cas9 need to be considered. Here, we used the syngeneic model of BAL17(CNS)-induced primary lymphoma of the central nervous system (PCNSL, CNS) in BALB/c mice to address this issue. Surprisingly, stable expression of Cas9 in BAL17(CNS) (BAL17(CNS)/Cas9) cells rendered them unable to establish PCNSL on intracerebral transplantation. Instead, they induced a prominent intracerebral immune response mediated by CD8 T cells, which lysed BAL17(CNS)/Cas9 cells via perforin. In addition, B cells contributed to the immune response as evidenced by serum anti-Cas9 antibodies in BALB/c mice as early as day 8 after transplantation of BAL17(CNS)/Cas9 cells. In athymic BALB/c(nu/nu) mice, NK cells mounted a vigorous intracerebral immune response with perforin-mediated destruction of BAL17(CNS)/Cas9 cells. Thus, in the CNS, perforin produced by NK and CD8 T cells was identified as a mediator of cytotoxicity against BAL17(CNS)/Cas9 cells. These observations should be taken into account when considering therapeutic CRISPR-Cas9-mediated tumor cell manipulation for PCNSL.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Montesinos-Rongen, Manuel UNSPECIFIED UNSPECIFIED UNSPECIFIED Sanchez-Ruiz, Monica UNSPECIFIED UNSPECIFIED UNSPECIFIED Siebert, Susann UNSPECIFIED UNSPECIFIED UNSPECIFIED Winter, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Siebert, Reiner UNSPECIFIED UNSPECIFIED UNSPECIFIED Brunn, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Deckert, Martina UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-667694
DOI:	10.1089/crispr.2022.0049
Journal or Publication Title:	CRISPR J.
Volume:	5
Number:	5
Page Range:	S. 726 - 740
Date:	2022
Publisher:	MARY ANN LIEBERT, INC
Place of Publication:	NEW ROCHELLE
ISSN:	2573-1602
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HUMAN NATURAL-KILLER; IN-VIVO; REPEATS; DESTRUCTION Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/66769