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* Division of Cancer Immunotherapeutics and Tumor Immunology and
Division of Hematology and Hematopoietic Cell Transplantation at the City of Hope National Medical Center and Beckman Research Institute, Duarte, CA 91010
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 (
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Institutes of Health (R01-CA103959); Michael Hoefflin Foundation, Ronald Flax Memorial Pediatric Cancer Research Fund; The Estelle, Abe, and Marjorie Sanders California Foundation; and Cancer Center Support Grant (5P30-CA33572-21). M.C.J. is a recipient of the Stop Cancer Foundation Career Development Award. C.E.B. is a Leukemia and Lymphoma Society of America Research Fellow.
2 Address correspondence and reprint requests to Dr. Christine Brown, Division of Cancer Immunotherapeutics and Tumor Immunology, City of Hope National Medical Center, KCRB 3009, 1500 East Duarte Road, Duarte, CA 91010. E-mail address: cbrown{at}coh.org
3 Abbreviations used in this paper: TIL, tumor-infiltrating lymphocyte; c-CSF, control cerebrospinal fluid; i.c., intracerebral; IP-10, IFN-
-inducible protein 10; rh, recombinant human; GBM, glioblastoma multiforme.
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