Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2015 Sep 15;21(18):4073-4085.
doi: 10.1158/1078-0432.CCR-14-2742. Epub 2015 Apr 28.

Myeloid-Derived Suppressor Cells as an Immune Parameter in Patients with Concurrent Sunitinib and Stereotactic Body Radiotherapy

Hui-Ming Chen #  1 , Ge Ma #  1 , Neil Gildener-Leapman  2 , Samuel Eisenstein  1   3 , Brian A Coakley  1   3 , Junko Ozao  1   3 , John Mandeli  4 , Celia Divino  3 , Myron Schwartz  3 , Max Sung  5 , Robert Ferris  2 , Johnny Kao  6 , Lu-Hai Wang  7 , Ping-Ying Pan  1 , Eric C Ko  1   8   9 , Shu-Hsia Chen  1   3
Affiliations
Clinical Trial

Myeloid-Derived Suppressor Cells as an Immune Parameter in Patients with Concurrent Sunitinib and Stereotactic Body Radiotherapy

Hui-Ming Chen et al. Clin Cancer Res. .

Abstract

Purpose: 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.

Experimental design: 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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Different MDSC subpopulations increased in normal and cancer patients. Peripheral blood mononuclear cells were purified from normal healthy donors and cancer patients. A, cytometric (left) and statistical (right) analysis of CD33+CD11b+ myeloid cell and CD33+CD15+ granulocytic MDSC percentages. B, cytometric (left) and statistical (right) analysis of CD33+ myeloid cells and CD14+CD16− and CD14+CD16+ subpopulation (in CD33+ myeloid cells) percentages. (*, P < 0.05; **, P < 0.01; ***, P < 0.001, when compared with normal healthy donors).
Figure 2
Figure 2
Sunitinib attenuates the M2-like phenotype in mouse MDSC and suppressive function in CD33+CD14+CD16+ nonclassical monocytes. Human PBMC or sorted human CD33+CD14+CD16+ nonclassical monocytes were left untreated (CT) or treated with sunitinib (SU, 250 nmol/L) for 48 hours followed by staining with indicated antibodies and isotype controls. A, total PBMCs were gated on CD33+ cells, and the dot plots of cell populations (left) and the statistical analyses of the percentages of CD33+CD14+CD16+ population (right) were presented. B, flow-cytometric histogram of Annexin V in total PBMC untreated (CT, black) or treated with sunitinib (SU, gray; left). Mean fluorescent intensity of CD206+ in Annexin V+CD33+CD14+CD16+ cells was shown in the right panel. C, flow-cytometric histograms (left) and mean fluorescent intensity (right) of pSTAT3+, CD206+, arginase+ (M2-like), and iNOS+ (M1-like) in sorted human CD33+CD14+CD16+ nonclassical monocytes. (*, P < 0.05, when compared with control group). D, human CD33+CD14+CD16− classical and CD33+CD14+CD16+ nonclassical monocytic populations were sorted from PBMC of patients before and after sunitinib treatment. Suppressive activity of CD33+CD14+CD16− and CD33+CD14+CD16+ populations in PBMC was assessed as described in Materials and Methods. (*, P < 0.05; **, P < 0.01, when compared with CD33+CD14+CD16− group before sunitinib treatment at indicated ratio.)
Figure 3
Figure 3
Concurrent sunitinib treatment and SBRT leads to decreases in MDSC population frequencies. PBMCs were obtained from patients enrolled in the clinical trials at time point A (pre-sunitinib treatment), time point B (7 days post-sunitinib treatment), and time point C (6–30 days post-SBRT). The cell numbers of specific cell populations in total cancer patients (left) and responders (middle) or nonresponders (right) based on sunitinib responsiveness; CD33+CD11b+ (A), CD33+HLA-DR−/low (B), CD33+CD14+CD16+ (C), and CD33+CD14+CD16− (D). The radiotherapy alone control group (E) was also analyzed pretreatment (time point A) and after radiation therapy (time point C) (F) The numbers of arginase expressing (top) and pSTAT3+ (bottom) cells in the CD33+CD14+CD16+ and CD33+CD14+CD16− populations are shown. (*, P < 0.05; **, P < 0.01).
Figure 3
Figure 3
Concurrent sunitinib treatment and SBRT leads to decreases in MDSC population frequencies. PBMCs were obtained from patients enrolled in the clinical trials at time point A (pre-sunitinib treatment), time point B (7 days post-sunitinib treatment), and time point C (6–30 days post-SBRT). The cell numbers of specific cell populations in total cancer patients (left) and responders (middle) or nonresponders (right) based on sunitinib responsiveness; CD33+CD11b+ (A), CD33+HLA-DR−/low (B), CD33+CD14+CD16+ (C), and CD33+CD14+CD16− (D). The radiotherapy alone control group (E) was also analyzed pretreatment (time point A) and after radiation therapy (time point C) (F) The numbers of arginase expressing (top) and pSTAT3+ (bottom) cells in the CD33+CD14+CD16+ and CD33+CD14+CD16− populations are shown. (*, P < 0.05; **, P < 0.01).
Figure 4
Figure 4
Sunitinib responders had a markedly reduced Treg population. The total cell number of CD4+CD25+CD127low Treg (A) and CD33−CD11b−CD19+CD5+ B cells (B) in PBMC from all patients, sunitinib-responders, and sunitinib-nonresponders based on the myeloid cell-based classification were presented. C, the percentages of Tbet-expressing CD4 (left) or CD8 (right) T cells were analyzed by flow cytometry. D, proliferative responses of PBMC obtained from patients at different time points. E, the radiotherapy alone control group was also analyzed before treatment (time point A) and after radiotherapy (time point C). (*, P < 0.05; **, P < 0.01).
Figure 5
Figure 5
Sunitinib-responsive patients based on CD33+CD11b+ myeloid cells exhibited prolonged clinical survival. Patients were divided into sunitinib-responders and nonresponders based on changes in their CD33+CD11b+ myeloid cell population, (Responders, n = 8; Non-responders, n = 11; A) or Tbet+ T-cell population (Responders, n = 10; Nonresponders, n = 9; B), as described in the Materials and Methods. Kaplan–Meier analysis on PFS (top), CSS (middle), and OS (bottom) stratified by sunitinib responsiveness were presented.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Tree AC, Khoo VS, Eeles RA, Ahmed M, Dearnaley DP, Hawkins MA, et al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol. 2013;14:e28–37. - PubMed
    1. Milano MT, Katz AW, Zhang H, Okunieff P. Oligometastases treated with stereotactic body radiotherapy: long-term follow-up of prospective study. Int J Radiat Oncol Biol Phys. 2012;83:878–86. - PubMed
    1. Seiwert TY, Salama JK, Vokes EE. The concurrent chemoradiation paradigm–general principles. Nat Clin Pract Oncol. 2007;4:86–100. - PubMed
    1. Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925–31. - PMC - PubMed
    1. Roskoski R., Jr Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem Biophys Res Commun. 2007;356:323–8. - PubMed

Publication types

MeSH terms