Compositions and methods for reducing C/EBP homologous protein activity in myeloid-derived suppressor cells
Provided are compositions and methods of use thereof that modulate C/EBP homologous stress-related protein (Chop) activity in Myeloid-derived Suppressor Cells (MDSCs). Chop is a key point in the response of MDSCs to tumor-generated stress factors. In turn, the MDSCs release cytokines and other factors that function as immune suppressors, thereby allowing the tumors to thrive and expand. By inhibiting the level of Chop activity, the immunosuppressive function of MDSCs is disrupted. It has also been unexpectedly found that there is a concomitant increase in the ability of MDSCs to act as antigen-presenting and cytokine producing cells so as to act in increasing the efficacy of anti-tumor immune-based therapies.
1. A method of reducing the level of activity of C/EBP-homologous protein (Chop) in a myeloid-derived suppressor cell (MDSC) or population of said cells, said method comprising delivering to a recipient MDSC or population of said recipient cells a composition comprising an siRNA, wherein the siRNA is an isolated double-stranded ribonucleic acid (dsRNA) molecule having either no overhang regions or at least one overhang region, wherein each overhang region contains six or fewer nucleotides, and wherein the dsRNA inhibits expression by a cell of a Chop protein, and wherein a first strand of the dsRNA is substantially identical to the sequence according to SEQ ID NO: 1, and a second strand is substantially complementary to the first that reduces the activity of Chop in the cell(s), and a vehicle for delivery of the agent to the interior of the recipient cell.
2. The method of claim 1 , wherein the agent is an siRNA and results in gene silencing of the Chop gene in the recipient MDSC or population of MDSCs.
3. The method of claim 1 , wherein the first strand of the dsRNA has a nucleotide sequence comprising SEQ ID NO: 1.
4. The method of claim 1 , wherein the vehicle is a liposome.
5. The method of claim 1 , wherein the vehicle is a pegylated-liposome.
6. The method of claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier.
7. The method of claim 1 , wherein the recipient MDSC or population of said recipient cells are isolated from an animal or human subject.
8. The method of claim 7 , wherein the isolated MDSC or population of said recipient cells are cultured cells.
9. A composition comprising an siRNA agent that when delivered to a myeloid-derived suppressor cell (MDSC) or population of said cells reduces the level of expression of a Chop-encoding gene, thereby reducing the level of Chop in the cell or cells, wherein the siRNA is an isolated double-stranded ribonucleic acid (dsRNA) molecule having either no overhang regions or at least one overhang region, wherein each overhang region contains six or fewer nucleotides, and wherein the dsRNA inhibits expression by a cell of a Chop protein, and wherein a first strand of the dsRNA is substantially identical to the sequence according to SEQ ID NO: 1, and a second strand is substantially complementary to the first.
10. The composition of claim 9 , further comprising a vehicle suitable for the delivery of the agent to the interior of the cell or cells.
11. The composition of claim 10 , wherein the vehicle is a liposome.
12. The composition of claim 10 , wherein the vehicle is a pegylated-liposome.
13. The composition of claim 9 , wherein the first strand of the dsRNA has the nucleotide sequence SEQ ID NO: 1.