Therapeutic efficacy of T cells derived from lymph nodes draining a poorly immunogenic tumor transduced to secrete granulocyte-macrophage colony-stimulating factor.
We examined the host immune response to the poorly immunogenic B16-BL6 melanoma, which was transduced to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) (450 ng/10(6)/24 h). Tumor growth after subcutaneous inoculation was not significantly altered, although an influx of neutrophils and monocytes/macrophages was evident within tumors and draining lymph nodes (LNs). Immunization with irradiated transduced cells did not induce systemic immunity to the parental tumor. However, vaccination with transduced tumors significantly augmented in vivo sensitization of draining LN cells. These tumor-draining LN (TDLN) cells, when secondarily stimulated in vitro with anti-CD3 monoclonal antibodies and expanded in interleukin-2 (10 U/ml), exhibited greater release of GM-CST and interferon-gamma against tumor compared with TDLN cells from animals with parental tumor. In adoptive immunotherapy, activated LN cells draining transduced tumors mediated significant reductions of the numbers of established pulmonary metastases compared with LN cells draining parental tumor, which were ineffective. In addition, the therapeutic efficacy of LN cells draining transduced tumors was significantly better than LN cells primed in vivo with tumor cells admixed with Corynebacterium parvum, which we have previously described as an approach to generate immune cells. Thus, GM-CSF appears to be an important adjuvant in the induction of tumor immunity.
Arca
M J
MJ
Division of Surgical Oncology, University of Michigan, Ann Arbor 48109, USA.
Krauss
J C
JC
Aruga
A
A
Cameron
M J
MJ
Shu
S
S
Chang
A E
AE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001483:Base Sequence; D017252:CD3 Complex / Q000276:immunology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism*; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology*; D008285:Major Histocompatibility Complex / Q000235:genetics; D008546:Melanoma, Experimental / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007376:Interleukin-2; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor