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.
Highlights
The recent success of some novel immunomodulatory regimen shed new light on immunotherapy as a promising approach for the treatment of cancer and chronic diseases
Preliminary experiments showed that mice receiving 676-1-25 tumor cell lysate as vaccine experienced a significant protection against live tumor cell challenge, that was more effective when the cell lysate was given in combination with CTX, administered one day before the vaccine (Supplementary Figure S2)
The requirement for a suitable animal model to address the open issues of chemo-immunotherapy often collides with the limitations of transplantable murine cancer cell lines, not faithfully recapitulating human cancer [22]
Summary
The recent success of some novel immunomodulatory regimen shed new light on immunotherapy as a promising approach for the treatment of cancer and chronic diseases. Besides the unfortunate balance between the rapid tumor growth and the slow development of a tumor-specific immune response, it has to be underlined that cancer cells set up several immune evasion strategies, by creating an immunosuppressive microenvironment www.impactjournals.com/oncotarget through the recruitment of regulatory T cells (Tregs) and other immune suppressors, or by selecting less immunogenic tumor variants [3, 4]. Different strategies have been employed in clinical and pre-clinical studies to improve the anti-tumor immune response, including infusion of tumor-infiltrating lymphocytes (TILs), lymphokine-activated killer cells (LAKs), vaccine-primed lymphocytes, T cells genetically engineered to express tumor-specific antigen receptors, and T cells with chimeric antigen receptors (CARs) [1]. The most promising results have been accomplished in clinics by immunotherapy approaches aimed at breaking tumor-induced tolerance, in particular by passive immunotherapy based on T-cells checkpoints restraint [5]
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