Sunitinib-induced myeloid lineage redistribution in renal cell cancer patients: CD1c+ dendritic cell frequency predicts progression-free survival.
OBJECTIVE
A disturbed myeloid lineage development with abnormally abundant neutrophils and impaired dendritic cell (DC) differentiation may contribute to tumor immune escape. We investigated the effect of sunitinib, a tyrosine kinase inhibitor of fms-like tyrosine kinase-3, KIT, and vascular endothelial growth factor receptors, on myeloid differentiation in renal cell cancer (RCC) patients.


METHODS
Twenty-six advanced RCC patients were treated with sunitinib in a 4-week on/2-week off schedule. Enumeration and extensive phenotyping of myeloid subsets in the blood was done at baseline and at weeks 4 and 6 of the first treatment cycle. Baseline patient data were compared with sex- and age-matched healthy donor data.


RESULTS
Baseline frequencies of DC subsets were lower in RCC patients than in healthy donors. After 4 weeks of sunitinib treatment, a generalized decrease in myeloid frequencies was observed. Whereas neutrophils and monocytes, which were both abnormally high at baseline, remained low during the 2-week off period, DC rates recovered, resulting in a normalized myeloid lineage distribution. Subsequent to sunitinib treatment, an increase to high levels of myeloid DC (MDC) subset frequencies relative to other myeloid subsets, was specifically observed in patients experiencing tumor regression. Moreover, high CD1c/BDCA-1(+) MDC frequencies were predictive for tumor regression and improved progression-free survival.


CONCLUSIONS
The sunitinib-induced myeloid lineage redistribution observed in advanced RCC patients is consistent with an improved immune status. Immunologic recovery may contribute to clinical efficacy as suggested by the finding of highly increased MDC frequencies relative to other myeloid subsets in patients with tumor regression.
van Cruijsen
Hester
H
Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
van der Veldt
Astrid A M
AA
Vroling
Laura
L
Oosterhoff
Dinja
D
Broxterman
Henk J
HJ
Scheper
Rik J
RJ
Giaccone
Giuseppe
G
Haanen
John B A G
JB
van den Eertwegh
Alfons J M
AJ
Boven
Epie
E
Hoekman
Klaas
K
de Gruijl
Tanja D
TD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018949:Antigens, CD1 / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D019070:Cell Lineage; D003713:Dendritic Cells / Q000276:immunology*; D018572:Disease-Free Survival; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D022423:Myeloid Cells / Q000276:immunology*; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D000077210:Sunitinib
D018949:Antigens, CD1; C437944:CD1C protein, human; D006023:Glycoproteins; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib