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RESEARCH PRODUCT

Abstract 4740: Doxorubicin eliminates tumor-induced myeloid-derived suppressor cells and enhances T-helper lymphocyte-based immunotherapy in a murine breast cancer model.

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Abstract Myeloid-derived suppressor cells (MDSC) represent a heterogeneous population of cells equipped with the ability to inhibit T lymphocyte-mediated immune responses. A significant increase in the number of MDSC has been reported in the blood, secondary lymphoid organs and tumor beds in tumor-bearing animals and in patients with many types of cancers. MDSC frequency correlates with the disease stage and prognosis. These cells impair CD8+ cytotoxic T lymphocyte (CTL)-mediated anti-tumor immunity by different overlapping mechanisms such as reactive oxygen species or immunosuppressive cytokine production. Importantly, MDSC elimination or inactivation substantially enhances the efficiency of immunotherapy. Multiple studies have lent support to the concept that some anti-neoplastic molecules, besides their conventional direct cytotoxic influence on cancer cells, may also exhibit immunostimulatory effects, thereby promoting anti-tumor immunity. We present results demonstrating that doxorubicin, utilized in multiple chemotherapeutic regimens and known to trigger an immunogenic type of cancer cell death, dramatically reduces the number of tumor-induced MDSC in the murine mammary tumor model 4T1. Elimination of these suppressive cells occurs by an apoptotic process. In addition, residual MDSC isolated from doxorubicin-treated animals are significantly impaired in their immunosuppressive function. Of particular interest, the number of apoptotic CD4+ or CD8+ T lymphocytes is not augmented in mice administered with doxorubicin compared to untreated animals. We further demonstrate that doxorubicin-mediated elimination of MDSC is associated with enhanced T and NK cell activation, proliferation and expression of Perforin and Granzyme B. Lastly, we evaluated a chemoimmunotherapeutic strategy associating doxorubicin with T helper-1 or T helper-17 lymphocytes generated and activated in vitro. Our results indicate that this combination regimen hinders tumor development as evidenced by reduced number of 4T1 metastatic nodules in the lungs of treated animals. This therapeutic effect is associated with an increased cytotoxic activity of CD8+ T lymphocytes in the spleen of the treated mice. These observations thus highlight a new application of doxorubicin as a MDSC depleting agent and further advocate for the implementation of this drug in cancer immunotherapy approaches. Citation Format: Darya Alizadeh, Malika Trad, Emmanuel Katsanis, Nicolas Larmonier. Doxorubicin eliminates tumor-induced myeloid-derived suppressor cells and enhances T-helper lymphocyte-based immunotherapy in a murine breast cancer model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4740. doi:10.1158/1538-7445.AM2013-4740