Tumor-derived chemokine MCP-1/CCL2 is sufficient for mediating tumor tropism of adoptively transferred T cells.
To exert a therapeutic effect, adoptively transferred tumor-specific CTLs must traffic to sites of tumor burden, exit the circulation, and infiltrate the tumor microenvironment. In this study, we examine the ability of adoptively transferred human CTL to traffic to tumors with disparate chemokine secretion profiles independent of tumor Ag recognition. Using a combination of in vivo tumor tropism studies and in vitro biophotonic chemotaxis assays, we observed that cell lines derived from glioma, medulloblastoma, and renal cell carcinoma efficiently chemoattracted ex vivo-expanded primary human T cells. We compared the chemokines secreted by tumor cell lines with high chemotactic activity with those that failed to elicit T cell chemotaxis (Daudi lymphoma, 10HTB neuroblastoma, and A2058 melanoma cells) and found a correlation between tumor-derived production of MCP-1/CCL2 (> or =10 ng/ml) and T cell chemotaxis. Chemokine immunodepletion studies confirmed that tumor-derived MCP-1 elicits effector T cell chemotaxis. Moreover, MCP-1 is sufficient for in vivo T cell tumor tropism as evidenced by the selective accumulation of i.v. administered firefly luciferase-expressing T cells in intracerebral xenografts of tumor transfectants secreting MCP-1. These studies suggest that the capacity of adoptively transferred T cells to home to tumors may be, in part, dictated by the species and amounts of tumor-derived chemokines, in particular MCP-1.
Brown
Christine E
CE
Division of Cancer Immunotherapeutics and Tumor Immunology, City of Hope National Medical Center and Beckham Research Institute, 1500 East Duarte Road, Duarte, CA 91010, USA. cbrown@coh.org
Vishwanath
Reena P
RP
Aguilar
Brenda
B
Starr
Renate
R
Najbauer
Joseph
J
Aboody
Karen S
KS
Jensen
Michael C
MC
D019264:Adoptive Transfer; D000818:Animals; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D018925:Chemokines / Q000032:analysis / Q000378:metabolism; D002633:Chemotaxis / Q000276:immunology*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation*; D018523:Tropism; D023041:Xenograft Model Antitumor Assays
D018932:Chemokine CCL2; D018925:Chemokines