Sunitinib is a
receptor tyrosine kinase inhibitor (TKI) that is front-line
therapy for metastatic
renal cell carcinoma (mRCC). Its antitumor activity is related to its ability to block
tumor cell and
tumor vasculature cell signaling via several TKI receptors (i.e.
vascular endothelial growth factor receptors VEGFRs, platelet-derived
growth factors (PDGFs), and stem cell factors).
Sunitinib also targets myeloid derived suppressor cells (MDSCs) significantly reducing their accumulation in the peripheral blood and reversing T cell (IFNγ) suppression in both mRCC patients and in murine
tumor models. This reduction in immune suppression provides a rationale for combining
sunitinib with
immunotherapy for the treatment of certain
tumor types. Despite these encouraging findings, however, we have observed that
sunitinib has variable impact at reducing MDSCs and restoring T cell function within the tumor microenvironment. Given the immunosuppressive and proangiogenic activities of MDSC, it seems plausible that their persistence may contribute to the resistance that develops in
sunitinib-treated patients. While
sunitinib reduced
tumor infiltrating MDSCs in Renca and CT26-bearing mice, coinciding with strong to modest decreases in
tumor size respectively, it was ineffective at reducing MDSCs (<35% reduction in Gr1+CD11b+) or
tumor burden in 4T1-bearing mice. Persistence of intratumor MDSCs was paralleled by depressed intratumor T cell IFNγ response and increased
GM-CSF expression. Additionally, in vitro and in vivo experiments showed that
GM-CSF prolongs survival of MDSCs, thus protecting them from the effects of
sunitinib via a pSTAT5-dependent pathway. Although preliminary, there is evidence of intratumor MDSC resistance in some mRCC patients following
sunitinib treatment. Intratumor MDSC persistence and T cell IFNγ response post
nephrectomy in patients receiving
sunitinib in a neoadjuvant setting are being compared to RCC patients undergoing
nephrectomy without prior
sunitinib treatment.
Tumors from untreated patients showed suppressed T cell IFNγ response along with substantial expression of MDSCs (5% of total digested cells). Thus far,
tumors from 5/8 neoadjuvant patients showed persistence of intratumor MDSCs and low T cell IFNγ production post
sunitinib treatment, findings that parallel results from untreated
tumors. In the remaining 3 neoadjuvant patients, intratumor MDSCs were detected at low levels which coincided with a T cell IFNγ response similar to that observed with normal donor peripheral T cells.
GM-CSF's role in promoting MDSC survival in patient
tumors is supported by the observation that
GM-CSF is produced in short-term RCC cultures at levels capable of protecting MDSCs from
sunitinib-induced cell death. Additionally, persistence of MDSC also may be associated with increased expression of proangiogenic
proteins, such as MMP9, MMP8, and
IL-8 produced by
tumor stromal cells or infiltrating MDSCs. Indeed our findings suggest that the most dominate MDSC subset in RCC patients is the neutrophilic population that produces proangiogenic
proteins. We propose that the development of
sunitinib resistance is partly mediated by the survival of MDSCs intratumorally, thereby providing sustained immune suppression and angiogenesis.