Compositions and methods for inhibiting tumor-induced immune suppression

Abstract

It has been discovered that the cyclic peptide EnnA inactivates the Hsp90 chaperone pathway, but without activating an extensive heat shock response and overexpression of anti-apoptotic proteins. Mechanistically distinct, EnnA inhibits Hsp90 and destabilize PDL-1 and IDO, two major immune checkpoints mediating tumor-induced immune suppression. The provided herein show that EnnA profoundly modulates the cytokine signature of cancer cells and promotes a cytokine profile that favors an immune attack on tumor cells. This translates into highly efficacious anti-tumor activity in vivo, which, when combined with a single dose of chemotherapy, completely reduced the tumor burden in experimental animals and instilled highly efficient immune memory against the primary tumor.

We claim: 
     
         1 . A pharmaceutical composition comprising:
 EnnA and a potentiating agent, chemotherapeutic agent or both.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the potentiating agent comprises cyclophosphamide. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the composition is formulated for enteral administration. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the composition is formulated for parenteral administration. 
     
     
         5 . A method for reducing tumor burden in a subject in need thereof, comprising:
 administering to the subject an effective amount of a composition comprising EnnA optionally in combination or alternation with a potentiating agent, chemotherapeutic agent, or both.   
     
     
         6 . The method of  claim 5 , wherein the effective amount of the composition inhibits or reduces proliferation of T regulatory cells and MDSCs in tumor microenvironments. 
     
     
         7 . The method of  claim 5 , wherein the effective amount of the composition reduces the mRNA and protein levels of Programmed death-ligand 1. 
     
     
         8 . The method of  claim 5 , wherein the effective amount of the composition inhibits the Hsp90 machine but does not induce an extensive cellular stress response. 
     
     
         9 . The method of  claim 5 , wherein the effective amount of the composition reduces proliferation of regulatory T cells and MDSCs in tumor microenvironments. 
     
     
         10 . The method of  claims 5 , wherein the effective amount of the composition reduces the number of CD4+Foxp3+ T regulatory cells (Tregs) and CD11b+Gr-1+ MDSCs in tumors. 
     
     
         11 . The method of  claim 5 , wherein the effective amount of the composition increases the immunogenicity of tumor cells. 
     
     
         12 . The method of  claim 5 , wherein the effective amount increases the immunogenic cell death. 
     
     
         13 . The method of  claim 5 , wherein the effective amount of the composition induces or promotes immune memory. 
     
     
         14 . The method of  claim 5 , wherein the potentiating agent comprises cyclophosphamide. 
     
     
         15 . A method for inhibiting infiltration of regulatory T cells and MDSCs into tumor microenvironments comprising administering to a subject in need thereof and effective amount of Enniantin A, optionally in combination or alternation with a potentiating agent, a chemotherapeutic agent, or both. 
     
     
         16 . The method of  claim 15 , wherein the potentiating agents comprises cyclophosphamide. 
     
     
         17 . A method for increasing immune memory to tumor antigens, comprising administering to a subject in need thereof and effective amount of EnnA, optionally in combination or alternation with a potentiating agent, chemotherapeutic agent or both. 
     
     
         18 . The method of  claim 16 , wherein the potentiating agent comprises cyclophosphamide.