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

KB Kim, AD Skora, Z Li, Q Liu, AJ Tam… - Proceedings of the …, 2014 - National Acad Sciences
KB Kim, AD Skora, Z Li, Q Liu, AJ Tam, RL Blosser, LA Diaz Jr, N Papadopoulos, KW Kinzler
Proceedings of the National Academy of Sciences, 2014National Acad Sciences
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 …
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.
National Acad Sciences