Journal
ONCOIMMUNOLOGY
Volume 7, Issue 8, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2018.1450715
Keywords
Genetic engineering; Adoptive cell therapy; ACT; T cells; Chemokine receptor; CXCR2; IL-8; Malignant melanoma
Categories
Funding
- Danish Cancer Society [R72-A4396-13-S2]
- Danish Council for Independent Research [DFF-1331-00095B]
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Adoptive cell therapy (ACT) using in vitro expanded tumor infiltrating T lymphocytes (TILs) from biopsy material represents a highly promising treatment of disseminated cancer. A crucial prerequisite for successful ACT is sufficient recruitment of transferred lymphocytes to the tumor site; however, despite infusion of billions of lymphocytes, T cell infiltration into the tumor post ACT is limited. By PCR and Luminex analyses we found that a majority of malignant melanoma (MM) cell lines expressed chemokines CXCL1/Gro, CXCL8/IL-8, CXCL12/SDF-1 and CCL2. Concerning expression of the corresponding receptors on T cells, only the IL-8 receptor, CXCR2, was not expressed on T cells. CXCR2 was therefore expressed in T cells by lentiviral transduction, and shown to lead to ligand specific transwell migration of engineered T cells, as well as increased migration towards MM conditioned medium. In vivo homing was assessed in a xenograft NOG mouse model. Mice with subcutaneous human melanoma were treated with MAGE-A3 specific T cells transduced with either CXCR2 or MOCK. Transducing T cells carrying the MAGE-A3(a3a) high affinity T cell receptor with CXCR2 increased tumor infiltration. Flow cytometry analysis 7days after ACT showed a doubling in CD3(+) T cells in tumor digest of mice receiving CXCR2 transduced T cells compared to MOCK treated mice, a finding confirmed by immunohistochemistry. In conclusion, our CXCR2 transduced T cells are functional in vitro and transduction with CXCR2 increases in vivo homing of T cells to tumor site.
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