Suppression of myeloid derived suppressor cells and immune checkpoint blockade

Abstract

Impressive responses have been observed in patients treated with checkpoint inhibitory anti-PD-1 or anti-CTLA-4 antibodies. However, immunotherapy against poorly immunogenic cancers remains a challenge. Treatment with both anti-PD-1 and anti-CTLA-4 antibodies were unable to eradicate large, modestly immunogenic CT26 tumors or metastatic 4T1 tumors. However, co-treatment with epigenetic modulating drugs and checkpoint inhibitors markedly improved treatment outcomes, curing more than 80% of them. 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 cured 80% of mice with metastatic 4T1 tumors when combined with immune checkpoint inhibitors. Thus, cancers resistant to immune checkpoint blockade can be cured by eliminating MDSCs.

1 - 66 . (canceled) 
     
     
         67 . A method of treating a mammal with a bacterial or viral infection, comprising:
 administering at least one agent which suppresses myeloid derived suppressor cells (MDSCs), wherein the agent is selected from the group consisting of a histone deacetylase inhibitor, a DNA methyltransferase inhibitor, a p110α subunit of phosphoinositol 3 kinase (PI3K) inhibitor, and combinations thereof.   
     
     
         68 . The method of  claim 67 , wherein the agent is a histone deacetylase inhibitor and the histone deacetylase inhibitor is entinostat. 
     
     
         69 . The method of  claim 67 , wherein the agent is a DNA methyltransferase inhibitor and the DNA methyltransferase inhibitor is 5-azacytadine. 
     
     
         70 . The method of  claim 67 , wherein the agent is a p110α subunit of phosphoinositol 3 kinase (PI3K) inhibitor and the p110α subunit of phosphoinositol 3 kinase (PI3K) inhibitor is J32. 
     
     
         71 . The method of  claim 67 , wherein the infection is a chronic viral infection. 
     
     
         72 . he method of  claim 67 , wherein the infection is bacterial with associated sepsis.