Tumor-driven accumulation of myeloid-derived suppressor cells (MDSC) facilitates tumor immune evasion via T-cell inhibition, therefore limiting therapeutic approaches. MDSC accumulate in tumor-bearing hosts via several factors, and suppress type-1 T-cell function via multiple mechanisms. Elevated MDSC in the blood of renal cell carcinoma patients, were first shown to significantly decline following treatment with sunitinib (inhibits VEGFr, ckit, flt3, PDGFr) treatment. This decline was correlated with a recovery in patients’ T-cell function, an effect which could be reproduced with in vitro MDSC depletion. Sunitinib induced MDSC apoptosis in vitro. Sunitinib-mediated declines in MDSC occurred even in non-responder patients and were not correlated with tumor shrinkage.
Studies in several murine tumor models confirmed sunitinib’s ability to universally inhibit peripheral MDSC accumulation and restore normal splenic T-cell function, even when sunitinib had negligible impacts on tumor progression. Sunitinib directly inhibited pathologic expansion of mononuclear m-MDSC, and directly reduced the viability of neutrophilic n-MDSC- which was pathologically extended in the tumor-bearing state. MDSC in bone marrow and tumor proved resistant to sunitinib however, and GM-CSF availability predicted sunitinib resistance. Recombinant GM-CSF could confer sunitinib resistance to MDSC in vitro. MDSC conditioning with GM-CSF inhibited STAT3 and promoted STAT5 activation, whereas other hematopoietic support factors preferentially preserved STAT3 activation and sunitinib susceptibility.
In vitro activation of MDSC from healthy human whole blood with tumor-conditioned media (TCM), further implicated GM-CSF, as well as gangliosides, in MDSC activation and survival. Sunitinib could indirectly inhibit MDSC activation, via drug-mediated reductions in ganglioside production by tumor cells. The phenotypic and functional resemblance of TCM-induced MDSC to mRCC patient MDSC indicated that this model of n-MDSC activation from a subset of normal neutrophils may be a contributing mechanism to MDSC accumulation in tumor-bearing hosts.
Sunitinib’s anti-MDSC activities at each of three steps were thus described. Increased MDSC expansion, activation, and viability all proved to contribute to MDSC accumulation. The drug’s ability to act at each of these three steps was limited in the presence of GM-CSF. Ancillary strategies to build upon sunitinib’s potency both as an immunomodulator and as a cancer therapy will be further investigated in future studies.