Chemo-immunotherapy induces tumor regression in a mouse model of spontaneous mammary carcinogenesis.

Abstract

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.

• Authors: Eleonora Aricò, Paola Sestili, Giulia Carpinelli, Rossella Canese, Serena Cecchetti, Giovanna Schiavoni, Maria Teresa D'Urso, Filippo Belardelli, Enrico Proietti
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 37 Pg. 59754-59765 (Sep 13 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27486759 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Alkylating
• Cyclophosphamide
• Receptor, ErbB-2

Topics

• Animals
• Antineoplastic Agents, Alkylating (administration & dosage)
• Cell Line, Tumor
• Cyclophosphamide (administration & dosage)
• Disease Models, Animal
• Female
• Humans
• Immunotherapy, Adoptive (methods)
• Mammary Neoplasms, Experimental (genetics, immunology, therapy)
• Mice, 129 Strain
• Mice, Transgenic
• Rats
• Receptor, ErbB-2 (genetics, immunology)
• Treatment Outcome