Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained.
The antiangiogenic drug sunitinib is a receptor tyrosine kinase inhibitor with significant, yet not curative, therapeutic effects in metastatic renal cell carcinoma (RCC). Sunitinib is also an immunomodulator, potently reversing myeloid-derived suppressor cell (MDSC) accumulation and T-cell inhibition in the blood even of nonresponder RCC patients. We observed that sunitinib similarly prevented MDSC accumulation and restored normal T-cell function to the spleens of tumor-bearing mice, independent of the capacity of sunitinib to inhibit tumor progression (RENCA>CT26>4T1). Both monocytic and neutrophilic splenic MDSC were highly repressible by sunitinib. In contrast, MDSC within the microenvironment of 4T1 tumors or human RCC tumors proved highly resistant to sunitinib and ambient T-cell function remained suppressed. Proteomic analyses comparing tumor to peripheral compartments showed that granulocyte macrophage colony-stimulating factor (GM-CSF) predicted sunitinib resistance and recombinant GM-CSF conferred sunitinib resistance to MDSC in vivo and in vitro. MDSC conditioning with GM-CSF uniquely inhibited signal transducers and activators of transcription (STAT3) and promoted STAT5 activation. STAT5ab(null/null) MDSC were rendered sensitive to sunitinib in the presence of GM-CSF in vitro. We conclude that compartment-dependent GM-CSF exposure in resistant tumors may account for the regionalized effect of sunitinib upon host MDSC modulation and hypothesize that ancillary strategies to decrease such regionalized escape will enhance the potency of sunitinib as an immunomodulator and a cancer therapy.
Ko
Jennifer S
JS
Department of Immunology, Taussig Cancer Institute, and Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Rayman
Patricia
P
Ireland
Joanna
J
Swaidani
Shadi
S
Li
Geqiang
G
Bunting
Kevin D
KD
Rini
Brian
B
Finke
James H
JH
Cohen
Peter A
PA
D000818:Animals; D039481:CD11b Antigen / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib; D013491:Suppressor Factors, Immunologic / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology
D039481:CD11b Antigen; D007155:Immunologic Factors; D007211:Indoles; D011758:Pyrroles; D013491:Suppressor Factors, Immunologic; D000077210:Sunitinib
Blood. 2008 Sep 1;112(5):1832-43
18577706
Nat Biotechnol. 2007 Aug;25(8):911-20
17664940
Blood. 2009 Mar 19;113(12):2805-15
19064728
Cancer Cell. 2009 Mar 3;15(3):220-31
19249680
N Engl J Med. 2008 Jun 19;358(25):2704-15
18565863
Clin Cancer Res. 2009 Mar 15;15(6):2148-57
19276286
Biochem Biophys Res Commun. 2007 May 4;356(2):323-8
17367763
J Clin Oncol. 2007 Jun 20;25(18):2546-53
17577033
J Immunol. 2009 May 1;182(9):5693-701
19380816
Cancer Cell. 2004 Oct;6(4):409-21
15488763
J Immunol. 2007 Jul 15;179(2):977-83
17617589
J Exp Med. 2002 Sep 2;196(5):619-28
12208877
Nat Rev Cancer. 2008 Aug;8(8):618-31
18633355
Immunol Rev. 2008 Apr;222:162-79
18364001
J Clin Oncol. 2006 Jan 1;24(1):25-35
16314617
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17069-74
17942672
Cancer Cell. 2009 Mar 3;15(3):232-9
19249681
Blood. 2006 Dec 1;108(12):3682-90
16888100
Cancer Res. 1990 Sep 1;50(17):5531-6
2386958
Blood. 2008 Apr 15;111(8):4233-44
18272812
Cancer Cell. 2008 Jan;13(1):23-35
18167337
J Immunol. 2008 Oct 15;181(8):5791-802
18832739
J Exp Med. 2008 Sep 29;205(10):2235-49
18809714
Cancer Res. 1993 Mar 15;53(6):1380-7
8443817
J Immunol. 2009 May 15;182(10):6562-8
19414811
Immunol Rev. 2008 Apr;222:180-91
18364002
Cancer Res. 2001 Jun 15;61(12):4756-60
11406548
Nat Rev Immunol. 2009 Mar;9(3):162-74
19197294
Expert Opin Pharmacother. 2007 Oct;8(14):2359-69
17927489
Clin Cancer Res. 2008 Oct 15;14(20):6674-82
18927310
Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6742-7
19346489
J Immunol. 2002 Nov 1;169(9):4811-21
12391191
Nat Rev Cancer. 2008 Aug;8(8):592-603
18650835
J Immunol. 2009 Apr 15;182(8):4499-506
19342621
Cancer Res. 2009 Mar 15;69(6):2506-13
19244102
Annu Rev Immunol. 2007;25:267-96
17134371
Cancer Res. 2005 Apr 15;65(8):3044-8
15833831
Clin Cancer Res. 2003 Jan;9(1):327-37
12538485
JAMA. 2006 Jun 7;295(21):2516-24
16757724
Cancer Res. 2009 Mar 15;69(6):2514-22
19276342
Cancer Res. 2009 Feb 15;69(4):1553-60
19201693
Blood. 2008 Jan 1;111(1):219-28
17885078
Cancer Res. 2004 Sep 1;64(17):6337-43
15342423
Blood. 2010 Feb 18;115(7):1416-24
20008792
J Immunol. 2001 Jan 1;166(1):678-89
11123353
Gastroenterology. 2008 Jul;135(1):234-43
18485901
J Clin Invest. 2008 Oct;118(10):3367-77
18776941