Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells

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Abstract
Impressive responses have been observed in patients treated with checkpoint inhibitory anti–programmed cell death-1 (PD-1) or anti–cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies. However, immunotherapy against poorly immunogenic cancers remains a challenge. Here we report that treatment with both anti–PD-1 and anti–CTLA-4 antibodies was unable to eradicate large, modestly immunogenic CT26 tumors or metastatic 4T1 tumors. Cotreatment with epigenetic-modulating drugs and checkpoint inhibitors markedly improved treatment outcomes, curing more than 80% of the tumor-bearing mice. Functional studies revealed that the primary targets of the epigenetic modulators were myeloid-derived suppressor cells (MDSCs). A PI3K inhibitor that reduced circulating MDSCs also eradicated 4T1 tumors in 80% of the mice when combined with immune checkpoint inhibitors. Thus, cancers resistant to immune checkpoint blockade can be cured by eliminating MDSCs. Significance Recent clinical trials have shown highly promising responses in a subset of patients treated with immune checkpoint inhibitory anti–programmed cell death-1, anti–programmed cell death ligand-1, and anti–cytotoxic T-lymphocyte-associated antigen-4 antibodies, but the majority of patients in these trials remained unresponsive. Our results show that elevated myeloid-derived suppressor cells(MDSCs) are responsible for the resistance and that elimination of MDSCs can lead to cures of experimental, metastatic tumors.