Global targeting of MDSC escape mechanisms cures advanced 4T1 breast tumors (P2062)

Abstract

Abstract 4T1 is a metastatic breast cancer model with fulminant accumulation of MDSCs. Survival and function of MDSCs is often reported as STAT3-dependent, and STAT3 inhibitors such as sunitinib dramatically deplete 4T1 splenic MDSCs. Paradoxically, sunitinib fails to eradicate 4T1 intratumoral MDSCs or prevent tumor progression. We hypothesized that STAT3 activation is a consistent feature of splenic but not intratumoral MDSCs. PhosphoSTAT analyses of 4T1-bearers confirmed that splenic MDSCs of all Gr1 intensities were solely pSTAT3pos. In remarkable contrast, intratumoral Gr1high MDSCs largely lacked any pSTAT activation, and intratumoral Gr1dim MDSC precursors displayed varied expression of pSTAT5 and pSTAT1 in addition to pSTAT3. We therefore sought global means to target MDSCs. We determined that 4T1 and other tumor models could be cured by repetitive administration of cyclophosphamide alternating with TLR agonists such as CpG ODN1826. While cure required participation of host CD4+ and CD8+ T cells, global targeting of MDSCs was also observed: (1) as with sunitinib, pSTAT3pos splenic MDSCs were eradicated; (2) pSTAT expression by intratumoral MDSCs was fully abolished; (3) the remaining intratumoral MDSCs, all pSTATneg, outsurvived all other cells, and were likely induced to serve as the final mediators of tumor rejection. In conclusion, strategies which globally target MDSCs and promote the endogenous anti-tumor T cell response can cure advanced metastatic tumors.