Chimeric Antigen Receptor T Cell Therapy Targeting Epithelial Cell Adhesion Molecule in Gastric Cancer: Mechanisms of Tumor Resistance.
Chimeric Antigen Receptor T Cell Therapy Targeting Epithelial Cell Adhesion Molecule in Gastric Cancer: Mechanisms of Tumor Resistance.
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DOI：
10.3390/cancers15235552
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发表时间：
2023-11-23
期刊：
影响因子：
5.2
通讯作者：
Jin, Moonsoo M.
中科院分区：
文献类型：
--
作者：
Yang, Yanping;Louie, Raymond;Puc, Janusz;Vedvyas, Yogindra;Alcaina, Yago;Min, Irene M.;Britz, Matt;Luciani, Fabio;Jin, Moonsoo M.
肿瘤获得对嵌合抗原受体（CAR） T细胞治疗耐药的具体机制尚不完全清楚。本研究的目的是阐明肿瘤细胞与靶向上皮细胞粘附分子（EpCAM）的CAR - T细胞在胃癌异种移植模型中的复杂相互作用。利用全身CAR - T细胞成像和单细胞多组学分析，我们注意到，在耐药肿瘤中，CAR - T细胞表现出增殖的倾向，但它们在很大程度上功能失调，失去了有效对抗癌症的能力。具体来说，大多数CD8 T细胞在肿瘤内耗尽，而CD4 T细胞转化为可以抑制免疫反应的调节性T细胞。此外，耐药的肿瘤细胞有特定的基因变化，可以促进癌症的生长，使疾病更难以治愈。这项研究为了解肿瘤如何抵抗CAR - T细胞治疗提供了有价值的信息，并可能指导癌症治疗的未来发展。上皮细胞粘附分子（Epithelial cell adhesion molecule, EpCAM）是一种肿瘤相关抗原，在多种肿瘤中经常过表达。我们已经开发出靶向EpCAM的CAR - T细胞用于胃癌的治疗。这项研究试图揭示肿瘤逃避免疫监视并对CAR - T细胞治疗产生耐药性的确切机制。通过结合全身CAR - T细胞成像和单细胞多组学分析，我们揭示了肿瘤和肿瘤浸润淋巴细胞（til）之间复杂的相互作用。在胃癌模型中，肿瘤浸润的CD8 T细胞表现出细胞毒性和耗竭表型，而CD4 T细胞主要是调节性T细胞。T细胞受体（TCR）克隆分析提供了CAR - T细胞在耐药肿瘤内增殖和克隆扩增的证据，这得到了全身CAR - T细胞成像的证实。此外，单细胞转录组学研究显示，在难愈或复发的小鼠肿瘤细胞中，参与主要组织相容性复合体（MHC）和抗原递呈途径、干扰素-γ和干扰素-α反应、线粒体活性以及与肿瘤进展和不利疾病预后相关的一组基因（如CD74、IDO1、IFI27）的基因富集。这项研究强调了一种结合成像和多组学方法来同时表征肿瘤进化和CAR - T细胞分化的方法。
The specific mechanisms by which tumors acquire resistance to chimeric antigen receptor (CAR) T cell therapy are not completely understood. The aim of this study was to elucidate the complex interactions between tumor cells and CAR T cells targeting epithelial cell adhesion molecule (EpCAM) in a xenograft model of gastric cancer. Using whole-body CAR T cell imaging and single-cell multiomic analyses, we noticed that within resistant tumors, CAR T cells exhibited a tendency to proliferate, but they were largely dysfunctional, losing their ability to fight cancer effectively. Specifically, most CD8 T cells became exhausted within tumors, while CD4 T cells transformed into regulatory T cells that can dampen the immune response. Additionally, the resistant tumor cells had specific gene changes that could promote cancer growth and make the disease more challenging to cure. This research provides valuable information for understanding how tumors resist CAR T cell therapy and may guide future developments in cancer treatment. Epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen that is frequently overexpressed in various carcinomas. We have developed chimeric antigen receptor (CAR) T cells specifically targeting EpCAM for the treatment of gastric cancer. This study sought to unravel the precise mechanisms by which tumors evade immune surveillance and develop resistance to CAR T cell therapy. Through a combination of whole-body CAR T cell imaging and single-cell multiomic analyses, we uncovered intricate interactions between tumors and tumor-infiltrating lymphocytes (TILs). In a gastric cancer model, tumor-infiltrating CD8 T cells exhibited both cytotoxic and exhausted phenotypes, while CD4 T cells were mainly regulatory T cells. A T cell receptor (TCR) clonal analysis provided evidence of CAR T cell proliferation and clonal expansion within resistant tumors, which was substantiated by whole-body CAR T cell imaging. Furthermore, single-cell transcriptomics showed that tumor cells in mice with refractory or relapsing outcomes were enriched for genes involved in major histocompatibility complex (MHC) and antigen presentation pathways, interferon-γ and interferon-α responses, mitochondrial activities, and a set of genes (e.g., CD74, IDO1, IFI27) linked to tumor progression and unfavorable disease prognoses. This research highlights an approach that combines imaging and multiomic methodologies to concurrently characterize the evolution of tumors and the differentiation of CAR T cells.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
82.9
作者：
Deng Q;Han G;Puebla-Osorio N;Ma MCJ;Strati P;Chasen B;Dai E;Dang M;Jain N;Yang H;Wang Y;Zhang S;Wang R;Chen R;Showell J;Ghosh S;Patchva S;Zhang Q;Sun R;Hagemeister F;Fayad L;Samaniego F;Lee HC;Nastoupil LJ;Fowler N;Eric Davis R;Westin J;Neelapu SS;Wang L;Green MR
通讯作者：
Green MR
影响因子：
64.5
作者：
Good CR;Aznar MA;Kuramitsu S;Samareh P;Agarwal S;Donahue G;Ishiyama K;Wellhausen N;Rennels AK;Ma Y;Tian L;Guedan S;Alexander KA;Zhang Z;Rommel PC;Singh N;Glastad KM;Richardson MW;Watanabe K;Tanyi JL;O'Hara MH;Ruella M;Lacey SF;Moon EK;Schuster SJ;Albelda SM;Lanier LL;Young RM;Berger SL;June CH
通讯作者：
June CH
影响因子：
82.9
作者：
Good, Zinaida;Spiegel, Jay Y.;Mackall, Crystal L.
通讯作者：
Mackall, Crystal L.
影响因子：
82.9
作者：
Haradhvala, Nicholas J.;Leick, Mark B.;Maurer, Katie;Gohil, Satyen H.;Larson, Rebecca C.;Yao, Ning;Gallagher, Kathleen M. E.;Katsis, Katelin;Frigault, Matthew J.;Southard, Jackson;Li, Shuqiang;Kann, Michael C.;Silva, Harrison;Jan, Max;Rhrissorrakrai, Kahn;Utro, Filippo;Levovitz, Chaya;Jacobs, Raquel A.;Slowik, Kara;Danysh, Brian P.;Livak, Kenneth J.;Parida, Laxmi;Ferry, Judith;Jacobson, Caron;Wu, Catherine J.;Getz, Gad;Maus, Marcela, V
通讯作者：
Maus, Marcela, V