A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers.
OBJECTIVE
Myeloid-derived suppressor cells (MDSC) accumulate in tumor-bearing hosts and are associated with immune suppression. To date, there have only been few studies that evaluate the direct effect of chemotherapeutic agents on MDSCs. Agents that inhibit MDSCs may be useful in the treatment of patients with various cancers.


METHODS
We investigated the in vivo effects of docetaxel on immune function in 4T1-Neu mammary tumor-bearing mice to examine if a favorable immunomodulatory effect accompanies tumor suppression. Primary focus was on the differentiation status of MDSCs and their ability to modulate T-cell responses.


RESULTS
Docetaxel administration significantly inhibited tumor growth in 4T1-Neu tumor-bearing mice and considerably decreased MDSC proportion in the spleen. The treatment also selectively increased CTL responses. Docetaxel-pretreated MDSCs cocultured with OT-II splenocytes in the presence of OVA(323-339) showed OT-II-specific CD4 activation and expansion in vitro. In characterizing the phenotype of MDSCs for M1 (CCR7) and M2 [mannose receptor (CD206)] markers, MDSCs from untreated tumor bearers were primarily MR(+) with few CCR7(+) cells. Docetaxel treatment polarized MDSCs toward an M1-like phenotype, resulting in 40% of MDSCs expressing CCR7 in vivo and in vitro, and macrophage differentiation markers such as MHC class II, CD11c, and CD86 were upregulated. Interestingly, docetaxel induced cell death selectively in MR(+) MDSCs while sparing the M1-like phenotype. Finally, inhibition of signal transducer and activator of transcription 3 may in part be responsible for the observed results.


CONCLUSIONS
These findings suggest potential clinical benefit for the addition of docetaxel to current immunotherapeutic protocols.
Kodumudi
Krithika N
KN
Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida 33612, USA.
Woan
Karrune
K
Gilvary
Danielle L
DL
Sahakian
Eva
E
Wei
Sheng
S
Djeu
Julie Y
JY
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D000077143:Docetaxel; D005260:Female; D007108:Immune Tolerance / Q000276:immunology; D056747:Immunomodulation / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D043823:Taxoids / Q000494:pharmacology* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D043823:Taxoids; D000077143:Docetaxel