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Efficacious immunomodulatory activity of the chemokine stromal cell–derived factor 1 (SDF-1): local secretion of SDF-1 at the tumor site serves as T-cell chemoattractant and mediates T-cell–dependent antitumor responses

2002; Elsevier BV; Volume: 100; Issue: 5 Linguagem: Inglês

10.1182/blood.v100.5.1551.h81702001551_1551_1558

1528-0020

Kyriaki Dunussi‐Joannopoulos, Krystyna Zuberek, Kathlene Runyon, Robert G. Hawley, Anthony Wong, Jamie Erickson, Steve Herrmann, John P. Leonard,

T-cell and B-cell Immunology

The chemokine stromal cell–derived factor 1 (SDF-1) is essential for perinatal viability, B lymphopoiesis, and bone marrow myelopoiesis, and is a potent monocyte and T-lymphocyte chemoattractant. Interactions of SDF-1 with its receptor CXCR4 have been implicated in CD34+ cell migration and homing. Here it is shown that human SDF-1β (hSDF-1β) alone secreted by hSDF-1β–transduced tumor cells promotes efficacious antitumor responses. The murine C1498 leukemia and B16F1 melanoma models have been studied. For expression of hSDF-1β by tumor cells (SDF-tumor cells), packaging cell lines secreting retroviruses encoding hSDF-1β have been used. The results demonstrate that 50% (B16F1) and 90% (C1498) of naive mice injected with SDF-tumor cells reject their tumors. Prophylactic vaccination of naive mice with irradiated SDF-tumor cells leads to systemic immunity, and therapeutic vaccination leads to cure of established tumors. Mice that previously rejected live SDF-tumor cells are immune to the rejected tumor but susceptible to another tumor and have in vitro tumor-specific cytotoxic T lymphocyte (CTL) activity. SDF-tumor cells are not rejected by immunodeficientscid mice. Immunohistochemistry shows significant infiltration of SDF-1 tumors by T cells, and in vivo T-cell depletion studies indicate that CD4+ T cells are required for SDF-mediated tumor rejection. In conclusion, the present data suggest that SDF-1/CXCR4 interactions have the potential to regulate efficacious antitumor immune responses; exploitation of these interactions may lead to novel therapeutic interventions.