[HTML][HTML] Enhanced recruitment of genetically modified CX3CR1-positive human T cells into Fractalkine/CX3CL1 expressing tumors: importance of the chemokine …
I Siddiqui, M Erreni, M van Brakel, R Debets… - … for immunotherapy of …, 2016 - Springer
I Siddiqui, M Erreni, M van Brakel, R Debets, P Allavena
Journal for immunotherapy of cancer, 2016•SpringerBackground 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. Methods In this study, we investigated whether the in vivo tumor trafficking of activated …
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. Methods In this study, we investigated whether the in vivo tumor trafficking of activated …
Background
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.
Methods
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.
Results
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.
Conclusions
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.
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