Chemo-immunotherapy induces tumor regression in a mouse model of spontaneous mammary carcinogenesis
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Eleonora Aricò1,*, Paola Sestili1,*, Giulia Carpinelli2, Rossella Canese2, Serena Cecchetti2, Giovanna Schiavoni1, Maria Teresa D’Urso1, Filippo Belardelli1, Enrico Proietti1
1Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
2Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
*These authors have contributed equally to this work
Eleonora Aricò, email: firstname.lastname@example.org
Keywords: chemotherapy, immunotherapy, cancer, ACT, HER-2 mice
Received: April 19, 2016 Accepted: July 10, 2016 Published: July 28, 2016
Tumor-specific immune tolerance represents an obstacle for the development of effective anti-tumor immune responses through cancer vaccines. We here evaluated the efficacy of chemo-immunotherapy in breaking tumor-specific immune tolerance in an almost incurable mouse model of spontaneous carcinogenesis.
Transgenic HER-2/neu mice bearing large mammary tumors received the adoptive transfer of splenocytes and serum isolated from immune donors, with or without pre-conditioning with cyclophosphamide. Treatment efficacy was assessed by monitoring tumor growth by manual inspection and by magnetic resonance imaging. The same chemo-immunotherapy protocol was tested on tumor-free HER-2/neu mice, to evaluate the effects on tumor emergence.
Our data show that chemo-immunotherapy hampered carcinogenesis and caused the regression of large mammary tumor lesions in tumor-bearing HER-2/neu mice. The complete eradication of a significant number of tumor lesions occurred only in mice receiving cyclophosphamide shortly before immunotherapy, and was associated with increased serum anti HER-2/p185 antibodies and tumor leukocyte infiltration. The same protocol significantly delayed the appearance of mammary tumors when administered to tumor-free HER-2/neu mice, indicating that this chemo-immunotherapy approach acted through the elicitation of an effective anti-tumor immune response. Overall, our data support the immune-modulatory role of chemotherapy in overcoming cancer immune tolerance when administered at lymphodepleting non-myeloablative doses shortly before transfer of antigen-specific immune cells and immunoglobulins. These findings open new perspectives on combining immune-modulatory chemotherapy and immunotherapy to overcome immune tolerance in cancer patients.
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