1. Definitive activation of endogenous antitumor immunity by repetitive cycles of cyclophosphamide with interspersed Toll-like receptor agonists.
- Author
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Manrique SZ, Dominguez AL, Mirza N, Spencer CD, Bradley JM, Finke JH, Lee JJ, Pease LR, Gendler SJ, and Cohen PA
- Subjects
- Animals, Cell Line, Tumor, Female, Humans, Immunosuppressive Agents pharmacology, Interferon Inducers pharmacology, Interferon-gamma immunology, Interferon-gamma metabolism, Mammary Neoplasms, Experimental immunology, Mammary Neoplasms, Experimental metabolism, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Myeloid Cells drug effects, Myeloid Cells immunology, Myeloid Cells metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Toll-Like Receptors metabolism, Cyclophosphamide pharmacology, Mammary Neoplasms, Experimental drug therapy, Oligodeoxyribonucleotides pharmacology, Poly I-C pharmacology, T-Lymphocytes drug effects, Toll-Like Receptors agonists
- Abstract
Many cancers both evoke and subvert endogenous anti-tumor immunity. However, immunosuppression can be therapeutically reversed in subsets of cancer patients by treatments such as checkpoint inhibitors or Toll-like receptor agonists (TLRa). Moreover, chemotherapy can leukodeplete immunosuppressive host elements, including myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). We hypothesized that chemotherapy-induced leukodepletion could be immunopotentiated by co-administering TLRa to emulate a life-threatening infection. Combining CpG (ODN 1826) or CpG+poly(I:C) with cyclophosphamide (CY) resulted in uniquely well-tolerated therapeutic synergy, permanently eradicating advanced mouse tumors including 4T1 (breast), Panc02 (pancreas) and CT26 (colorectal). Definitive treatment required endogenous CD8+ and CD4+ IFNγ-producing T-cells. Tumor-specific IFNγ-producing T-cells persisted during CY-induced leukopenia, whereas Tregs were progressively eliminated, especially intratumorally. Spleen-associated MDSCs were cyclically depleted by CY+TLRa treatment, with residual monocytic MDSCs requiring only continued exposure to CpG or CpG+IFNγ to effectively attack malignant cells while sparing non-transformed cells. Such tumor destruction occurred despite upregulated tumor expression of Programmed Death Ligand-1, but could be blocked by clodronate-loaded liposomes to deplete phagocytic cells or by nitric oxide synthase inhibitors. CY+TLRa also induced tumoricidal myeloid cells in naive mice, indicating that CY+TLRa's immunomodulatory impacts occurred in the complete absence of tumor-bearing, and that tumor-induced MDSCs were not an essential source of tumoricidal myeloid precursors. Repetitive CY+TLRa can therefore modulate endogenous immunity to eradicate advanced tumors without vaccinations or adoptive T-cell therapy. Human blood monocytes could be rendered similarly tumoricidal during in vitro activation with TLRa+IFNγ, underscoring the potential therapeutic relevance of these mouse tumor studies to cancer patients., Competing Interests: The authors have no financial conflicts of interest.
- Published
- 2016
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