Research Papers: Immunology:

Definitive activation of endogenous antitumor immunity by repetitive cycles of cyclophosphamide with interspersed Toll-like receptor agonists

Soraya Zorro Manrique, Ana L. Dominguez, Noweeda Mirza, Christopher D. Spencer, Judy M. Bradley, James H. Finke, James J. Lee, Larry R. Pease, Sandra J. Gendler and Peter A. Cohen _

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Oncotarget. 2016; 7:42919-42942. https://doi.org/10.18632/oncotarget.10190

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Soraya Zorro Manrique1, Ana L. Dominguez1, Noweeda Mirza1, Christopher D. Spencer1, Judy M. Bradley1, James H. Finke2, James J. Lee3,4, Larry R. Pease1, Sandra J. Gendler1,3,5 and Peter A. Cohen1,5

1 Department of Immunology, Mayo Clinic in Arizona, Scottsdale, AZ, USA

2 Department of Immunology, Lerner Research Institute, Cleveland, OH, USA

3 Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona, Scottsdale, AZ, USA

4 Division of Pulmonary Medicine, Mayo Clinic in Arizona, Scottsdale, AZ, USA

5 Division of Hematology/Oncology, Mayo Clinic in Arizona, Scottsdale, AZ, USA

Correspondence to:

Peter A. Cohen, email:

Keywords: cancer immunotherapy, chemotherapy, TLR agonists, MDSCs, Tregs, Immunology and Microbiology Section, Immune response, Immunity

Received: February 17, 2016 Accepted: April 29, 2016 Published: June 21, 2016


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.

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