Department of Immunology and Inflammation, Humanitas Clinical and Research Center, 20089 Rozzano, Milan Italy ; Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland.
Department of Immunology and Inflammation, Humanitas Clinical and Research Center, 20089 Rozzano, Milan Italy.
J Immunother Cancer. 2016 Apr 19;4:21. doi: 10.1186/s40425-016-0125-1. eCollection 2016.
Adoptive T-cell based immunotherapies constitute a promising approach to treat cancer, however, a major problem is to obtain effective and long-lasting anti-tumor responses. Lack of response may be due to insufficient trafficking of specific T cells to tumors. A key requirement for efficient migration of cytotoxic T cells is that they express chemokine receptors that match the chemokines produced by tumor or tumor-associated cells.
In this study, we investigated whether the in vivo tumor trafficking of activated T cells could be enhanced by the expression of the chemokine receptor CX3CR1. Two human colorectal cancer cell lines were used to set up a xenograft tumor model in immunodeficient mice; the NCI-H630, constitutively expressing the chemokine ligand CX3CL1 (Fractalkine), and the RKO cell line, transduced to express CX3CL1.
Human primary T cells were transduced with the receptor CX3CR1-eGFP. Upon in vivo adoptive transfer of genetically modified CX3CR1-T cells in mice bearing NCI-H630 tumors, enhanced lymphocyte migration and tumor trafficking were observed, compared to mice receiving Mock-T cells, indicating improved homing ability towards ligand-expressing tumor cells. Furthermore, significant inhibition of tumor growth was found in mice receiving modified CX3CR1-T cells. In contrast, tumors formed by RKO cells transduced with the ligand (RKO-CX3CL1) were not affected, nor more infiltrated upon transfer of CX3CR1-T lymphocytes, likely because high levels of the chemokine were shed by tumor cells in the systemic circulation, thus nullifying the blood-tissue chemokine gradient.
This study demonstrates that ectopic expression of CX3CR1 enhanced the homing of adoptively transferred T cells towards CX3CL1-producing tumors, resulting in increased T cell infiltration in tumor tissues and decreased tumor growth. Our results also establish that a correct chemokine gradient between the systemic circulation and the tumor is an essential requirement in adoptive T-cell based immunotherapy to efficiently recruit T cell effectors at the correct sites.
过继性 T 细胞免疫疗法是治疗癌症的一种很有前途的方法，然而，一个主要的问题是获得有效的、持久的抗肿瘤反应。缺乏反应可能是由于特异性 T 细胞向肿瘤的转移不足。细胞毒性 T 细胞有效迁移的一个关键要求是它们表达与肿瘤或肿瘤相关细胞产生的趋化因子相匹配的趋化因子受体。
在这项研究中，我们研究了过表达趋化因子受体 CX3CR1 是否可以增强激活的 T 细胞在体内向肿瘤的迁移。我们使用了两种人结直肠癌细胞系来建立免疫缺陷小鼠的异种移植肿瘤模型；NCI-H630 细胞系持续表达趋化因子配体 CX3CL1（ fractalkine），RKO 细胞系转导表达 CX3CL1。
将受体 CX3CR1-eGFP 转导到人原代 T 细胞中。在 NCI-H630 肿瘤小鼠体内过继转移基因修饰的 CX3CR1-T 细胞后，观察到淋巴细胞迁移和肿瘤转移增强，与接受 Mock-T 细胞的小鼠相比，表明对表达配体的肿瘤细胞具有改善的归巢能力。此外，在接受修饰的 CX3CR1-T 细胞的小鼠中发现肿瘤生长明显受到抑制。相比之下，转导配体的 RKO 细胞（RKO-CX3CL1）形成的肿瘤不受影响，转导 CX3CR1-T 淋巴细胞后也没有更多的浸润，这可能是因为肿瘤细胞在全身循环中大量分泌趋化因子，从而使血液-组织趋化因子梯度失效。
本研究表明，CX3CR1 的异位表达增强了过继转移的 T 细胞向产生 CX3CL1 的肿瘤的归巢，导致肿瘤组织中 T 细胞浸润增加和肿瘤生长减少。我们的研究结果还表明，在过继性 T 细胞免疫治疗中，在全身循环和肿瘤之间建立正确的趋化因子梯度是有效招募 T 细胞效应器到正确部位的必要条件。
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