Inhibition of in vivo tumor growth by the beta chemokine, TCA3.
TCA3 is a proinflammatory murine glycoprotein that shares structural features with cytokines of the beta chemokine family and is a chemoattractant for neutrophils and monocytes. To assess the in vivo functions of TCA3, the cDNA was expressed in two mouse myeloma cell lines. Although the transfected and control cells had similar growth rates in vitro, TCA3-expressing tumors demonstrated impaired growth in both normal and immunodeficient mice. Histologic evaluation of the injection sites demonstrated that TCA3 expression resulted in an early neutrophil and monocyte infiltrate accompanied by tumor necrosis. There was complete regression of the TCA3-transfected tumor in some immunocompetent syngeneic mice. The TCA3-transfected cells induced specific and long-lasting immunity in mice that showed complete tumor regression; these animals were resistant to challenge with nontransfected tumor cells. In contrast, priming with irradiated tumor cells provided little protection against challenge with nontransfected tumor, which indicates that TCA3 specifically augments tumor immunogenicity. Mixing TCA3-transfected cells with normal tumor cells causes retarded growth of the normal tumor cells provided the latter are injected into the same site. Furthermore, direct in situ injection of soluble rTCA3 early during the course of tumor implantation also inhibits tumor growth. The data suggest that TCA3 may perform two roles in tumor protection: it induces lymphocyte-independent antitumor activity and stimulates tumor-specific immunity. We speculate that TCA3 has natural adjuvant activities that result in augmented immune responses.
Department of Pathology, Harvard Medical School, Boston, MA 02115.
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Laning
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Kawasaki
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Tanaka
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Luo
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Dorf
D000818:Animals; D054402:Chemokine CCL1; D019742:Chemokines, CC; D016207:Cytokines / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D009368:Neoplasm Transplantation / Q000276:immunology; D054401:Receptors, CCR8; D014162:Transfection
C065971:CCL1 protein, human; C489319:Ccr8 protein, mouse; D054402:Chemokine CCL1; D019742:Chemokines, CC; D016207:Cytokines; D054401:Receptors, CCR8