Compositions and methods for inhibiting tumor-induced immune suppression
View Patent ↗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.
1. A method for reducing cancer cells in a subject having breast cancer, hepatoma, glioma, lymphoma or leukemia, comprising:
administering to the subject an effective amount of a composition consisting of Enniatin A (EnnA) and
a single dose of a potentiating agent, chemotherapeutic agent, or both to inhibit a Hsp90 machine without inducing an extensive cellular stress response.
2. The method of claim 1 , wherein the effective amount of the composition inhibits or reduces proliferation of T regulatory cells and myeloid-derived suppressor cells (MDSCs) in tumor microenvironments.
3. The method of claim 1 , wherein the effective amount of the composition reduces the mRNA and protein levels of Programmed death-ligand 1.
4. The method of claim 1 , wherein the effective amount of the composition reduces proliferation of regulatory T cells and MDSCs in tumor microenvironments.
5. The method of claim 1 , wherein the effective amount of the composition reduces the number of CD4+Foxp3+ T regulatory cells (Tregs) and CD11b+Gr-1+ MDSCs in tumors.
6. The method of claim 1 , wherein the effective amount of the composition increases the immunogenicity of cancer cells.
7. The method of claim 1 , wherein the effective amount increases the immunogenic cell death.
8. The method of claim 1 , wherein the effective amount of the composition induces or promotes immune memory.
9. The method of claim 1 , wherein the potentiating agent comprises cyclophosphamide.
10. The method of claim 1 , wherein the effective amount of a composition consisting of Enniatin A (EnnA) is 5 μM to about 40 μM.