Inhibition of cytokine-induced SH2 protein in NK cells
The present invention relates to therapeutic and prophylactic methods based on inhibition of CIS in NK cells. In particular, the present invention relates to treating or preventing a NK-responsive condition by administering to a subject a CIS inhibitor, or administering CIS-inhibited NK cells. The invention further relates to methods for identifying a CIS inhibitor, and for determining a likelihood of cancer response to treatment with CIS inhibition.
1. CIS-inhibited human NK cells, wherein the CIS-inhibited human NK cells are genetically modified to have reduced expression of CIS, or are genetically modified to express a dominant negative CIS sequence variant or dominant negative fragment thereof.
2. The CIS-inhibited human NK cells of claim 1 , wherein the CIS-inhibited human NK cells are NK cells genetically modified to have reduced expression of CIS.
3. The CIS-inhibited human NK cells of claim 1 , wherein the CIS-inhibited human NK cells are Cish −/− .
4. The CIS-inhibited human NK cells of claim 1 , in which the Cish gene has been genetically deleted.
5. The CIS-inhibited human NK cells of claim 1 , wherein expression of CIS protein has been reduced by a gene silencing strategy.
6. The CIS-inhibited human NK cells of claim 5 , wherein the gene silencing strategy comprises use of siRNA or RNAi.
7. The CIS-inhibited human NK cells of claim 1 , wherein the CIS-inhibited human NK cells are genetically modified to express a dominant negative CIS sequence variant or dominant negative fragment thereof.
8. The CIS-inhibited human NK cells of claim 1 , wherein the CIS-inhibited human NK cells are irreversibly genetically modified.
9. The CIS-inhibited human NK cells of claim 1 , wherein the CIS-inhibited human NK cells are reversibly genetically modified so that over time the CIS inhibition in the NK cells decreases.
10. Human Cish −/+ NK cells.
11. Human Cish −/− NK cells.
12. A composition comprising the human Cish −/− NK cells of claim 11 .
13. A pharmaceutical composition comprising the human Cish −/− NK cells of claim 11 .