Chimeric antigen receptor engineered NK cellular immunotherapy overcomes the selection of T-cell escape variant cancer cells.
Chimeric antigen receptor engineered NK cellular immunotherapy overcomes the selection of T-cell escape variant cancer cells.
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嵌合抗原受体工程化 NK 细胞免疫疗法克服了 T 细胞逃逸变异癌细胞的选择。
DOI：
10.1136/jitc-2020-002128
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发表时间：
2021-03
影响因子：
10.9
通讯作者：
Allen C
中科院分区：
文献类型：
--
作者：
Lee MY;Robbins Y;Sievers C;Friedman J;Abdul Sater H;Clavijo PE;Judd N;Tsong E;Silvin C;Soon-Shiong P;Padget MR;Schlom J;Hodge J;Hinrichs C;Allen C
由于异质性肿瘤在完整免疫的情况下发展，因此选择具有有利于逃避T细胞检测或消除的基因组或表达缺陷的肿瘤细胞。对于患有这种肿瘤的患者，单独的基于T细胞的免疫疗法很少导致持久的肿瘤控制。在这里，我们开发了实验模型来研究T细胞逃逸的机制，并证明了对T细胞杀伤的抗性可以通过添加天然杀伤（NK）细胞来克服，这些细胞被工程化以表达靶向程序性死亡配体-1（PD-L1）的嵌合抗原受体（CAR）。在肿瘤异质性的工程模型中，PD-L1 CAR工程NK细胞（PD-L1 t-haNK）阻止了在多种模型中单独T细胞治疗时观察到的T细胞抗性肿瘤细胞的克隆选择。用T细胞处理异源癌细胞群导致干扰素γ（IFN-γ）释放，随后肿瘤细胞上的PD-L1上调，这些肿瘤细胞通过抗原加工和呈递缺陷逃避T细胞杀伤，在体外和体内引发逃逸细胞群通过PD-L1 t-haNK进行PD-L1依赖性杀伤。这些结果描述了基于T细胞的免疫治疗之间协同抗肿瘤活性的潜在机制，导致IFN-γ产生，T细胞逃逸细胞上PD-L1的上调，以及PD-L1 CAR工程NK细胞靶向和消除耐药肿瘤细胞群的用途。
As heterogeneous tumors develop in the face of intact immunity, tumor cells harboring genomic or expression defects that favor evasion from T-cell detection or elimination are selected. For patients with such tumors, T cell-based immunotherapy alone infrequently results in durable tumor control. Here, we developed experimental models to study mechanisms of T-cell escape and demonstrated that resistance to T-cell killing can be overcome by the addition of natural killer (NK) cells engineered to express a chimeric antigen receptor (CAR) targeting programmed death ligand-1 (PD-L1). In engineered models of tumor heterogeneity, PD-L1 CAR-engineered NK cells (PD-L1 t-haNKs) prevented the clonal selection of T cell-resistant tumor cells observed with T-cell treatment alone in multiple models. Treatment of heterogenous cancer cell populations with T cells resulted in interferon gamma (IFN-γ) release and subsequent upregulation of PD-L1 on tumor cells that escaped T-cell killing through defects in antigen processing and presentation, priming escape cell populations for PD-L1 dependent killing by PD-L1 t-haNKs in vitro and in vivo. These results describe the underlying mechanisms governing synergistic antitumor activity between T cell-based immunotherapy that results in IFN-γ production, upregulation of PD-L1 on T-cell escape cells, and the use of PD-L1 CAR-engineered NK cells to target and eliminate resistant tumor cell populations.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
64.8
作者：
Manguso RT;Pope HW;Zimmer MD;Brown FD;Yates KB;Miller BC;Collins NB;Bi K;LaFleur MW;Juneja VR;Weiss SA;Lo J;Fisher DE;Miao D;Van Allen E;Root DE;Sharpe AH;Doench JG;Haining WN
通讯作者：
Haining WN
影响因子：
64.8
作者：
Matsushita, Hirokazu;Vesely, Matthew D.;Koboldt, Daniel C.;Rickert, Charles G.;Uppaluri, Ravindra;Magrini, Vincent J.;Arthur, Cora D.;White, J. Michael;Chen, Yee-Shiuan;Shea, Lauren K.;Hundal, Jasreet;Wendl, Michael C.;Demeter, Ryan;Wylie, Todd;Allison, James P.;Smyth, Mark J.;Old, Lloyd J.;Mardis, Elaine R.;Schreiber, Robert D.
通讯作者：
Schreiber, Robert D.
影响因子：
45.3
作者：
Doran, Stacey L.;Stevanovic, Sanja;Hinrichs, Christian S.
通讯作者：
Hinrichs, Christian S.
影响因子：
28.4
作者：
Massarelli, Erminia;William, William;Glisson, Bonnie
通讯作者：
Glisson, Bonnie