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Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells #MMPMID25071169
Kim K; Skora AD; Li Z; Liu Q; Tam AJ; Blosser RL; Diaz LA Jr; Papadopoulos N; Kinzler KW; Vogelstein B; Zhou S
Proc Natl Acad Sci U S A 2014[Aug]; 111 (32): 11774-9 PMID25071169show ga
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.
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Proc+Natl+Acad+Sci+U+S+A 2014 ; 111 (32): 11774-9
