Journal
CANCER RESEARCH
Volume 74, Issue 1, Pages 104-118Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-13-1545
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Funding
- National Institutes of Health [R01CA104926]
- Cancer Biology Training Grant [T32CA009213]
- AZ Cancer Center Grant [CA023074]
- Cancer Center Support Grant [CA023074]
- PANDA Funds
- La Ligue contre le Cancer (Coordination interr egionale du Grand-Est)
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Myeloid-derived suppressor cells (MDSC) expand in tumor-bearing hosts and play a central role in cancer immune evasion by inhibiting adaptive and innate immunity. They therefore represent a major obstacle for successful cancer immunotherapy. Different strategies have thus been explored to deplete and/or inactivate MDSC in vivo. Using a murine mammary cancer model, we demonstrated that doxorubicin selectively eliminates MDSC in the spleen, blood, and tumor beds. Furthermore, residual MDSC from doxorubicin- treated mice exhibited impaired suppressive function. Importantly, the frequency of CD4(+) and CD8(+) T lymphocytes and consequently the effector lymphocytes or natural killer (NK) to suppressive MDSC ratios were significantly increased following doxorubicin treatment of tumor-bearing mice. In addition, the proportion of NK and cytotoxic T cell (CTL) expressing perforin and granzyme B and of CTL producing IFN-gamma was augmented by doxorubicin administration. Of therapeutic relevance, this drug efficiently combined with Th-1 or Th-17 lymphocytes to suppress tumor development and metastatic disease. MDSC isolated from patients with different types of cancer were also sensitive to doxorubicin-mediated cytotoxicity in vitro. These results thus indicate that doxorubicin may be used not only as a direct cytotoxic drug against tumor cells, but also as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression, thereby fostering the efficacy of T-cell-based immunotherapy. (C)2013 AACR.
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