Biofabrication of 3D breast cancer models for dissecting the cytotoxic response of human T cells expressing engineered MAIT cell receptors.
Biofabrication of 3D breast cancer models for dissecting the cytotoxic response of human T cells expressing engineered MAIT cell receptors.
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3D乳腺癌模型的生物制作，用于解剖表达工程Mait细胞受体的人T细胞的细胞毒性反应。
DOI：
10.1088/1758-5090/ac925a
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发表时间：
2022-09-29
期刊：
影响因子：
9
通讯作者：
Ozbolat, Ibrahim T.
中科院分区：
文献类型：
--
作者：
Dey, Madhuri;Kim, Myong Hwan;Nagamine, Momoka;Karhan, Ece;Kozhaya, Lina;Dogan, Mikail;Unutmaz, Derya;Ozbolat, Ibrahim T.
随着旨在降低全身毒性的靶向治疗的先进细胞工程技术的出现，免疫疗法彻底改变了癌症治疗。然而，了解潜在的免疫-癌症相互作用需要开发先进的人体组织三维（3D）模型。在这项研究中，我们制作了复杂性不断增加的3D肿瘤模型，以研究CD 8 + T细胞对MDA-MB-231乳腺癌细胞的细胞毒性反应，这些细胞经基因工程改造以表达粘膜相关的不变T（MAIT）细胞受体。用前体MAIT细胞配体5-氨基-6-D-核糖基氨基尿嘧啶（5-ARU）引发同型MDA-MB-231和异型MDA-MB-231/人真皮成纤维细胞（HDF）肿瘤球状体。工程化T细胞在3天的培养期后有效地消除肿瘤，表明工程化T细胞受体（TCR）在5-ARU存在下识别表达主要组织相容性复合物I类相关（MR 1）蛋白的肿瘤细胞。还通过将这些细胞包封在纤维蛋白中，模拟肿瘤细胞外基质微环境来评估工程化T细胞的肿瘤细胞杀伤效率。免疫治疗后，促炎细胞因子如IFNγ、IL-13、CCL-3的表达表明所有肿瘤模型中的免疫细胞活化。此外，在证实细胞毒活性时，我们发现颗粒酶A和B在同型和异型肿瘤中也上调。最后，采用3D生物打印肿瘤模型来研究T细胞相对于肿瘤的定位效果。在肿瘤近端生物打印的T细胞具有降低的侵袭指数和增加的细胞因子分泌，这表明免疫-癌症相互作用的旁分泌模式。3D肿瘤-T细胞平台的开发可能使研究复杂的免疫-癌症相互作用和工程化MAIT细胞用于基于细胞的癌症免疫治疗成为可能。
Immunotherapy has revolutionized cancer treatment with the advent of advanced cell engineering techniques aimed at targeted therapy with reduced systemic toxicity. However, understanding the underlying immune-cancer interactions require development of advanced three-dimensional (3D) models of human tissues. In this study, we fabricated 3D tumor models with increasing complexity to study the cytotoxic responses of CD8+ T cells, genetically engineered to express mucosal-associated invariant T (MAIT) cell receptors, towards MDA-MB-231 breast cancer cells. Homotypic MDA-MB-231 and heterotypic MDA-MB-231/human dermal fibroblast (HDF) tumor spheroids were primed with precursor MAIT cell ligand 5-amino-6-D-ribitylaminouracil (5-ARU). Engineered T cells effectively eliminated tumors after a 3-day culture period, demonstrating that the engineered T cell receptor (TCR) recognized major histocompatibility complex class I-related (MR1) protein expressing tumor cells in the presence of 5-ARU. Tumor cell killing efficiency of engineered T cells were also assessed by encapsulating these cells in fibrin, mimicking a tumor extracellular matrix microenvironment. Expression of proinflammatory cytokines such as IFNγ, IL-13, CCL-3 indicated immune cell activation in all tumor models, post immunotherapy. Further, in corroborating the cytotoxic activity, we found that granzymes A and B were also upregulated, in homotypic as well as heterotypic tumors. Finally, a 3D bioprinted tumor model was employed to study the effect of localization of T cells with respect to tumors. T cells bioprinted proximal to the tumor had reduced invasion index and increased cytokine secretion, which indicated a paracrine mode of immune-cancer interaction. Development of 3D tumor-T cell platforms may enable studying the complex immune-cancer interactions and engineering MAIT cells for cell-based cancer immunotherapies.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
12.8
作者：
Hong IS
通讯作者：
Hong IS
CXCL9是与ER阴性乳腺癌预后相关的免疫浸润的潜在生物标志物。
影响因子：
4.7
作者：
Liang YK;Deng ZK;Chen MT;Qiu SQ;Xiao YS;Qi YZ;Xie Q;Wang ZH;Jia SC;Zeng D;Lin HY
通讯作者：
Lin HY
DOI：
10.1007/978-3-030-36667-4_5
发表时间：
2020-01-01
期刊：
TUMOR MICROENVIRONMENT: THE ROLE OF CHEMOKINES, PT A
影响因子：
--
作者：
Neo, Shi Yong;Lundqvist, Andreas
通讯作者：
Lundqvist, Andreas
影响因子：
--
作者：
Jürgensen HJ;Silva LM;Krigslund O;van Putten S;Madsen DH;Behrendt N;Engelholm LH;Bugge TH
通讯作者：
Bugge TH