Sunitinib-Induced Myeloid Lineage Redistribution in Renal Cell Cancer Patients: CD1c+ Dendritic Cell Frequency Predicts Progression-Free Survival

Abstract

Purpose: 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. Experimental Design: 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. Conclusion: 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.

Monitoring peri-operative immune suppression in renal cancer patients

“…The implementation of a commercially available test kit for whole blood analysis without any separation step for the cell labeling resulted in a lower blood DC count (0.24% of leukocytes) when compared to other authors using density gradient separation of mononuclear cells (≥0.6% of leukocytes) (18). The blood DC were in particular low in patients with advanced tumor disease (≥pT3): DC correlated both with tumor staging and grading.…”

Effects of combined sunitinib and extracranial stereotactic radiotherapy on bone marrow hematopoiesis

“…One clear disadvantage of relatively non-specific inhibitors is the toxicity resulting from 'off target' effects of multi-targeted agents (21). Sunitinib has been associated with decreased leukocytes, lymphocytes, hemoglobin, monocytes, platelets, neutrophils and increased median corpuscular volume (16,(22)(23)(24). Clinicians are increasingly adopting more specific tyrosine kinase inhibitors that have lower rates of hematological toxicity (25).…”

“…An emerging body of research suggests that sunitinib mediates antitumor immunity through bone marrow-derived cells (8,13). For instance, flow cytometric characterization of changes before and after sunitinib administration suggest that the number of immunosuppressive monocytic MDSCs and T regulatory cells decreases, while myeloid dendritic cells increase (13,24).…”

Sunitinib‐induced changes in circulating endothelial cell‐related proteins in patients with metastatic renal cell cancer

“…Each patient signed a protocol-specific informed consent. Collection of data was part of three protocols, [16][17][18][19] which were approved by the medical ethics review boards of the institutes.…”