Trafficking of tumor peptide-specific cytotoxic T lymphocytes into the tumor microcirculation.
The major histocompatibility complex class I-restricted CD8(+) cytotoxic T-lymphocyte (CTL) effector arm of the adaptive immune response can specifically recognize and destroy tumor cells expressing peptide antigens. Although adoptive T-cell therapy has been successfully used for the treatment of viral and malignant diseases, little is known of the trafficking and fate of adoptively transferred antigen-specific T cells. In the present study, splenocytes derived from mice that rejected their tumors (CT26 or CT26-clone 25 tumors) in response to direct intratumor injection of disabled infectious single-cycle herpes simplex virus (DISC-HSV) encoding murine GM-CSF were restimulated with peptide in vitro. CTLs specific for the AH-1 and beta-gal peptides expressed by CT26 and CT26-clone 25 tumor cells, respectively, were generated and used for adoptive cellular therapy and trafficking studies. Intravenous administration of AH-1-specific CTLs 3 days following i.v. injection of CT26 cells resulted in significant tumor growth inhibition, whereas administration of control CTLs generated against a bacterial beta-gal peptide did not inhibit the growth of tumors. Trafficking of AH-1-specific lymphocytes and their interaction with the CT26 tumor microcirculation was analyzed using real-time in vivo microscopy (IVM). AH-1-specific but not beta-gal-specific CTLs adhered and localized in the CT26 tumor microvasculature, but neither population adhered to the endothelium of the normal microcirculation. This study provides direct visual evidence suggesting that AH-1-specific CTLs that mediate a therapeutic response traffic to and localize within the tumor microenvironment.
Ali
Selman
S
Interdisciplinary Biomedical Research Centre, School of Science, Nottingham Trent University, Nottingham, United Kingdom.
Ahmad
Murrium
M
Lynam
June
J
Rees
Robert C
RC
Brown
Nicola
N
D000818:Animals; D002465:Cell Movement; D005434:Flow Cytometry; D015316:Genetic Therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D016219:Immunotherapy, Adoptive; D051379:Mice; D008807:Mice, Inbred BALB C; D008833:Microcirculation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000276:immunology / Q000628:therapy*; D018139:Simplexvirus / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D016178:Granulocyte-Macrophage Colony-Stimulating Factor