Myeloid-Derived Suppressor Cells as an Immune Parameter in Patients with Concurrent Sunitinib and Stereotactic Body Radiotherapy.
OBJECTIVE
The clinical effects of sunitinib on human myeloid-derived suppressor cell (MDSC) subsets and correlation of the T-cell-mediated immune responses and clinical outcomes in patients with oligometastases treated by stereotactic body radiotherapy (SBRT) have been evaluated.


METHODS
The numbers of granulocytic and monocytic MDSC subsets, effector T cells, and regulatory T cells in the peripheral blood were evaluated pre- and post-sunitinib treatment and concurrent with SBRT. Correlations between MDSC, Treg, and T-cell responses and clinical outcomes were analyzed.


RESULTS
Patients with oligometastases of various cancer types had elevated granulocytic MDSC and certain subsets of monocytic MDSC population. Sunitinib treatment resulted in a significant reduction in monocytic MDSC, phosphorylated STAT3, and arginase levels in monocytic MDSC (CD33(+)CD14(+)CD16(+)), and an increase in T-cell proliferative activity in cancer patients. Interestingly, the effects of sunitinib on reducing the accumulation and immune-suppressive function of MDSC were significantly correlated with Treg reduction, in responders but not in nonresponding patients. SBRT synergized the therapeutic effects of sunitinib, especially as related to decreased numbers of monocytic MDSC, Treg, and B cells, and augmented Tbet expression in primary CD4 and CD8 T cells. These effects were not observed in patients receiving radiation therapy alone. Most interestingly, the responders, defined by sunitinib-mediated reduction in CD33(+)CD11b(+) myeloid cell populations, tend to exhibit improved progression-free survival and cause-specific survival.


CONCLUSIONS
Sunitinib treatment increased the efficacy of SBRT in patients with oligometastases by reversing MDSC and Treg-mediated immune suppression and may enhance cancer immune therapy to prevent tumor recurrence post-SBRT.
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York.
Hui-Ming
HM
Chen
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York.
Ge
G
Ma
Department of Otolaryngology and Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
Neil
N
Gildener-Leapman
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York.|Department of Surgery, Mount Sinai School of Medicine, New York, New York.
Samuel
S
Eisenstein
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York.|Department of Surgery, Mount Sinai School of Medicine, New York, New York.
Brian A
BA
Coakley
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York.|Department of Surgery, Mount Sinai School of Medicine, New York, New York.
Junko
J
Ozao
Department of Preventive Medicine, Mount Sinai School of Medicine, New York, New York.
John
J
Mandeli
Department of Surgery, Mount Sinai School of Medicine, New York, New York.
Celia
C
Divino
Department of Surgery, Mount Sinai School of Medicine, New York, New York.
Myron
M
Schwartz
Department of Medicine, Mount Sinai School of Medicine, New York, New York.
Max
M
Sung
Department of Otolaryngology and Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
Robert
R
Ferris
Department of Radiation Oncology, Good Samaritan Hospital Medical Center, West Islip, New York.
Johnny
J
Kao
Institute of Molecular and Genomic Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan.
Lu-Hai
LH
Wang
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York.
Ping-Ying
PY
Pan
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York.|Department of Radiation Oncology, Mercy UC Davis Cancer Center, Merced, California.|Department of Radiation Oncology, UC Davis Comprehensive Cancer Center, Sacramento, California.
Eric C
EC
Ko
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York.|Department of Surgery, Mount Sinai School of Medicine, New York, New York.
Shu-Hsia
SH
Chen
D000970:Antineoplastic Agents / Q000008:administration & dosage*; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D049109:Cell Proliferation; D002470:Cell Survival; D018450:Disease Progression; D005434:Flow Cytometry; D006801:Humans; D007107:Immune System; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007211:Indoles / Q000008:administration & dosage*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D009000:Monocytes / Q000166:cytology; D022423:Myeloid Cells / Q000166:cytology*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology / Q000532:radiotherapy* / Q000628:therapy*; D010766:Phosphorylation; D011758:Pyrroles / Q000008:administration & dosage*; D016634:Radiosurgery; D050796:STAT3 Transcription Factor / Q000378:metabolism; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000378:metabolism; D000077210:Sunitinib; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D039481:CD11b Antigen; D007166:Immunosuppressive Agents; D007211:Indoles; D011758:Pyrroles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3; D000077210:Sunitinib