Rejection of metastatic 4T1 breast cancer by attenuation of Treg cells in combination with immune stimulation.
4T1 breast carcinoma is a highly malignant and poorly immunogenic murine tumor model that resembles advanced breast cancer in humans, and is refractory to most immune stimulation-based treatments. We hypothesize that the ineffectiveness of immune stimulatory treatment is mediated by the suppressive effects of CD4(+)CD25(+) regulatory T (Treg) cells, which can be attenuated by engaging the glucocorticoid-induced tumor necrosis factor receptor family-related protein with its natural ligand (GITRL); further, combination treatment with existing immune stimulation regimens will augment anti-tumor immunity and eradicate metastatic 4T1 tumors in mice.A soluble homodimeric form of mouse GITRL (mIg-mGITRLs) was molecularly constructed and used to treat orthotopic 4T1 tumors established in immune-competent, syngeneic Balb/c mice. When applied in combination with adenovirus-mediated intratumoral murine granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-12 (IL-12) gene delivery plus systemic 4-1BB activation, mIg-mGITRLs attenuated the immune-suppressive function of splenic Treg cells, which led to elevated interferon-gamma (IFN-gamma) production, tumor-specific cytolytic T-cell activities, tumor rejection and long-term survival in 65% of the animals without apparent toxicities. The results demonstrate that addition of mIg-mGITRLs to an immune-stimulatory treatment regimen significantly improved long-term survival without apparent toxicity, and could potentially be clinically translated into an effective and safe treatment modality for metastatic breast cancer in patients.
Chen
Li
L
Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
Huang
Tian-Gui
TG
Meseck
Marcia
M
Mandeli
John
J
Fallon
John
J
Woo
Savio L C
SL
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000235:genetics; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000008:administration & dosage / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D017931:DNA Primers; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor