TCR-NK 细胞：肿瘤过继免疫治疗的新来源

Antigen-specific retargeting of cytotoxic lymphocytes against tumor-associated 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 and chains. It has been observed that the delivery of a second TCR / 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. 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 ve zincirlerinden olu an ligand ba lama b lgesinin heterodimerik yap s nedeniyle sorunludur. Genetik modifikasyon yoluyla iletilen yeni TCR ve 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 t