TCR-NK Cells: A Novel Source for Adoptive Immunotherapy of Cancer

TCR-NK Cells: A Novel Source for Adoptive Immunotherapy of Cancer [Turk J Hematol]

Turk J Hematol. 2023; 40(1): 1-10 | DOI: 10.4274/tjh.galenos.2022.2022.0534

TCR-NK Cells: A Novel Source for Adoptive Immunotherapy of Cancer

Zeynep Sena Karahan¹, Mertkaya Aras², Tolga S�tl�¹
¹Bo�azi�i University Faculty of Arts and Sciences, Department of Molecular Biology and Genetics, �stanbul, T�rkiye
²Bo�azi�i University Faculty of Arts and Sciences, Department of Molecular Biology and Genetics, �stanbul, T�rkiye; Sabanc� University Faculty of Engineering and Natural Sciences, Department of Molecular Biology, Genetics, and Bioengineering, �stanbul, T�rkiye

Antigen-specific retargeting of cytotoxic lymphocytes against tumorassociated antigens has thus far remained largely dependent on chimeric antigen receptors (CARs) that can be constructed by the fusion of an extracellular targeting domain (classically a single-chain variable fragment from an antibody) fused with intracellular signaling domains to trigger activation of T or natural killer (NK) cells. A major limitation of CAR-based therapies is that this technology only allows for the targeting of antigens that would be located on the surface of target cells while non-surface antigens, which affect approximately three-fourths of all human genes, remain out of reach. The targeting of non-surface antigens is only possible using inherent T cell receptor (TCR) mechanisms. However, introducing a second TCR into T cells via genetic modification is problematic due to the heterodimeric nature of the TCR ligand-binding domain, which is composed of TCR α and β chains. It has been observed that the delivery of a second TCR α/β pair may lead to the mispairing of new TCR chains with the endogenously expressed ones and create mixed TCR dimers, and this has negatively affected the advancement of TCR-based T cell therapies. Recently, NK cells have been put forward as possible effectors for TCR gene therapy. Since NK cells do not endogenously express TCR chains, this seems to be an infallible approach to circumventing the problem of mispairing. Moreover, the similarity of intracellular signaling pathways and mechanisms of cytotoxicity between NK and T cells ensures that the triggering of antigen-specific responses by the TCR/CD3 complex can be used to induce antigen-specific cytotoxicity by TCR-modified NK (TCR-NK) cells. This review provides an overview of the initial studies of TCR-NK cells, identifies open questions in the field, and defines the place of this approach within the spectrum of adoptive immunotherapy techniques that rely on cytotoxic lymphocytes.

Keywords: T-cell receptor, Natural killer cells, CAR-T cells, TCR-NK cells

Adoptif Kanser �mm�noterapisi i�in Yeni Bir Kaynak: TCR-NK H�creleri

Sitotoksik lenfositlerin genetik modifikasyon yoluyla t�m�r antijenlerine hedeflenerek kanser imm�noterapisi i�in kullan�lmas�, g�n�m�zde en yo�un olarak kimerik antijen resept�r� (CAR) teknolojisiyle uygulanmaktad�r. Bu teknolojide, t�m�r antijenini hedefleyen antikor dizilerinden elde edilen bir tek zincirli de�i�ken fragman, T veya do�al �ld�r�c� (NK) h�crelerin aktivasyonunu tetiklemek i�in h�cre i�i sinyal dizileriyle birle�tirilerek yeni bir resept�r tasarlanmaktad�r. CAR tabanl� tedaviler, yaln�zca hedefteki t�m�r h�crelerinin y�zeyinde yer alan antijenlerin hedeflenmesine izin verirken, t�m insan genlerinin yakla��k d�rtte ��n� olu�turan h�cre i�i antijenlerin bu teknoloji ile eri�ilemeyecek durumda olmas� �nemli bir eksikliktir. H�cre y�zeyinde bulunmayan antijenlerin hedeflenmesi, yaln�zca T-h�cre resept�r� (TCR) kullan�larak m�mk�n olmaktad�r. Bununla birlikte, genetik modifikasyon yoluyla T-h�crelerine ikinci bir TCR�nin transfer edilmesi, TCR α ve β zincirlerinden olu�an ligand ba�lama b�lgesinin heterodimerik yap�s� nedeniyle sorunludur. Genetik modifikasyon yoluyla iletilen yeni TCR α ve β zincirlerinin, endojen olarak ifade edilen zincirlerle yanl�� e�le�mesi sonucu kar��k TCR dimerleri olu�abilece�i g�zlemlenmi� ve bu sorun TCR ile modifiye T-h�cre tedavilerinin geli�tirilmesini olumsuz etkilemi�tir. Yak�n d�nemde, bu sorunun �stesinden gelmek amac�yla NK h�creleri, TCR gen terapisi i�in olas� efekt�r h�cre tipi olarak �ne s�r�lm��t�r. NK h�creleri, TCR zincirlerini endojen olarak ifade etmedi�inden, yanl�� e�le�me sorununun �stesinden gelmek i�in yan�lmaz bir yakla��m olarak g�r�nmektedir. NK ve T-h�creleri aras�ndaki h�cre i�i sinyal yolaklar�n�n ve sitotoksisite mekanizmalar�n�n benzerli�i sayesinde, TCR ile modifiye edilmi� NK (TCR-NK) h�crelerinde antijene �zg�l sitotoksisite ind�klemenin m�mk�n oldu�u g�sterilmi�tir. Bu derleme, TCR-NK h�creleriyle ilgili �nc�l �al��malar�n genel bir �zetini ileterek, alandaki a��k sorular� tan�mlamay� ve bu yeni yakla��m�n, sitotoksik lenfositlere dayal� adoptif imm�noterapi teknikleri yelpazesindeki yerini tan�mlamay� ama�lamaktad�r.

Anahtar Kelimeler: T-h�cre resept�r�, Do�al �ld�r�c� h�creler, CAR-T h�creleri, TCR-NK h�creler

Zeynep Sena Karahan, Mertkaya Aras, Tolga S�tl�. TCR-NK Cells: A Novel Source for Adoptive Immunotherapy of Cancer. Turk J Hematol. 2023; 40(1): 1-10

Corresponding Author: Tolga S�tl�, T�rkiye

TOOLS

Full Text PDF

Download citation

RIS

EndNote

BibTex

Medlars

Procite

Reference Manager

Share with email

Send email to author

Similar articles

PubMed

Google Scholar

In authors and institutes

In titles and abstracts

In keywords

In all


	E-ISSN: 1308-5263
Archive Most Accessed Articles Most Cited Articles Aims and Scope Instructions For Authors Editorial Board Advisory Board Manuscript Submission Why to Submit Search Contact