The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies.
In tumor-bearing hosts, myeloid-derived suppressor cells (MDSC) and T regulatory cells (Treg) play important roles in immune suppression, the reversal of which is vitally important for the success of immune therapy. We have shown that ckit ligand is required for MDSC accumulation and Treg development. We hypothesized that sunitinib malate, a receptor tyrosine kinase inhibitor, could reverse MDSC-mediated immune suppression and modulate the tumor microenvironment, thereby improving the efficacy of immune-based therapies. Treatment with sunitinib decreased the number of MDSC and Treg in advanced tumor-bearing animals. Furthermore, it not only reduced the suppressive function of MDSCs but also prevented tumor-specific T-cell anergy and Treg development. Interestingly, sunitinib treatment resulted in reduced expression of interleukin (IL)-10, transforming growth factor-beta, and Foxp3 but enhanced expression of Th1 cytokine IFN-gamma and increased CTL responses in isolated tumor-infiltrating leukocytes. A significantly higher percentage and infiltration of CD8 and CD4 cells was detected in tumors of sunitinib-treated mice when compared with control-treated mice. More importantly, the expression of negative costimulatory molecules CTLA4 and PD-1 in both CD4 and CD8 T cells, and PDL-1 expression on MDSC and plasmacytoid dendritic cells, was also significantly decreased by sunitinib treatment. Finally, sunitinib in combination with our immune therapy protocol (IL-12 and 4-1BB activation) significantly improves the long-term survival rate of large tumor-bearing mice. These data suggest that sunitinib can be used to reverse immune suppression and as a potentially useful adjunct for enhancing the efficacy of immune-based cancer therapy for advanced malignancies.
Ozao-Choy
Junko
J
Departments of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York, USA.
Ma
Ge
G
Kao
Johnny
J
Wang
George X
GX
Meseck
Marcia
M
Sung
Max
M
Schwartz
Myron
M
Divino
Celia M
CM
Pan
Ping-Ying
PY
Chen
Shu-Hsia
SH
D000595:Amino Acid Sequence; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D007211:Indoles / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology
D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D000077210:Sunitinib