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Primary 4T1 tumor resection provides critical “window of opportunity” for immunotherapy

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Abstract

It is believed that primary tumor resection modulates host-tumor immune interaction, but this has not been characterized in a stringent breast cancer tumor model. This report, using the 4T1 murine mammary tumor model, characterizes for the first time the dynamic longitudinal changes in immunosuppressive and effector components of the immune system after resection of an established orthotopic primary tumor with a defined natural history of developing lung metastases. More specifically, we analyzed changes of absolute numbers and frequencies of MDSC, regulatory T cells (Treg), as well as activated CD4 and CD8 positive T cells in spleens and, in some studies, lungs of 4T1 tumor-bearing mice and mice after primary tumor resection. Importantly, using mathematical analyses we established that primary resection of an orthotopic tumor had created a “window of opportunity” with decreased tumor-associated immune suppression that existed for approximately 10 days. Although tumor resection did slightly prolong survival, it did not affect the ultimate development of metastatic disease since animals with resected tumors or intact primary tumors eventually died by day 47 and 43, respectively. This window of opportunity likely occurs in humans providing a rationale and parameters for integration and testing of immunotherapeutic strategies in this critical “window of opportunity” to combat the development of metastatic disease.

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Abbreviations

MDSC:

Myeloid derived suppressor cells

TAA:

Tumor associated antigen

Treg:

Regulatory T cells

TD:

Tumor diameter

PMC:

Pulmonary mononuclear cells

DC:

Dendritic cells

TAM:

Tumor associated macrophages

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Acknowledgments

This work was supported by Susan Komen Foundation BCTR0707720 for E.L.N. and M.G.A., and in part by Award Number P30CA062203 from the National Cancer Institute. H.D. was supported by T32 training grant (AG000096) from the National Institute of Aging. We would like to thank Dr. Amanda Laust Anderson and Mr. Tigran Tiraturyan for help in some experimental procedures, Dr. Annette Marleau and Dr. Irina Petrushina for their valuable suggestions and editing of the manuscript.

Conflict of interest

Authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. Department of Molecular Immunology, Institute for Molecular Medicine, 16371 Gothard Street, Suite H, Huntington Beach, CA, 92647, USA

    Anahit Ghochikyan, Arpine Davtyan, Armine Hovakimyan, Hayk Davtyan, Anna Poghosyan & Michael G. Agadjanyan

  2. The Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, 92697, USA

    Hayk Davtyan & Michael G. Agadjanyan

  3. The Institute of Immunology, Moscow, Russia

    Alexander Bagaev & Ravshan I. Ataullakhanov

  4. Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, 92697, USA

    Edward L. Nelson

  5. Department of Medicine, Division of Hematology and Oncology, University of California, Irvine, CA, 92697, USA

    Edward L. Nelson

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  1. Anahit Ghochikyan
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  2. Arpine Davtyan
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  3. Armine Hovakimyan
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  4. Hayk Davtyan
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  6. Alexander Bagaev
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  9. Michael G. Agadjanyan
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Correspondence to Anahit Ghochikyan or Michael G. Agadjanyan.

Additional information

Michael G. Agadjanyan and Anahit Ghochikyan contributed equally to this work.

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Ghochikyan, A., Davtyan, A., Hovakimyan, A. et al. Primary 4T1 tumor resection provides critical “window of opportunity” for immunotherapy. Clin Exp Metastasis 31, 185–198 (2014). https://doi.org/10.1007/s10585-013-9619-0

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