In:
Advanced Science, Wiley, Vol. 10, No. 17 ( 2023-06)
Abstract:
HLA‐G is considered as an immune checkpoint protein and a tumor‐associated antigen. In the previous work, it is reported that CAR‐NK targeting of HLA‐G can be used to treat certain solid tumors. However, the frequent co‐expression of PD‐L1 and HLA‐G) and up‐regulation of PD‐L1 after adoptive immunotherapy may decrease the effectiveness of HLA‐G‐CAR. Therefore, simultaneous targeting of HLA‐G and PD‐L1 by multi‐specific CAR could represent an appropriate solution. Furthermore, gamma‐delta T ( γδ T) cells exhibit MHC‐independent cytotoxicity against tumor cells and possess allogeneic potential. The utilization of nanobodies offers flexibility for CAR engineering and the ability to recognize novel epitopes. In this study, V δ 2 γδ T cells are used as effector cells and electroporated with an mRNA‐driven, nanobody‐based HLA‐G‐CAR with a secreted PD‐L1/CD3 ε Bispecific T‐cell engager (BiTE) construct (Nb‐CAR.BiTE). Both in vivo and in vitro experiments reveal that the Nb‐CAR.BiTE‐ γδ T cells could effectively eliminate PD‐L1 and/or HLA‐G‐positive solid tumors. The secreted PD‐L1/CD3 ε Nb‐BiTE can not only redirect Nb‐CAR‐ γδ T but also recruit un‐transduced bystander T cells against tumor cells expressing PD‐L1, thereby enhancing the activity of Nb‐CAR‐ γδ T therapy. Furthermore, evidence is provided that Nb‐CAR.BiTE redirectes γδ T into tumor‐implanted tissues and that the secreted Nb‐BiTE is restricted to the tumor site without apparent toxicity.
Type of Medium:
Online Resource
ISSN:
2198-3844
,
2198-3844
DOI:
10.1002/advs.202206856
Language:
English
Publisher:
Wiley
Publication Date:
2023
detail.hit.zdb_id:
2808093-2
