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. A method for treating a subject suffering from a NK cell-responsive condition or at risk of suffering from a NK cell-responsive condition, comprising administering a phosphopeptide CIS inhibitor or a phosphomimetic peptide CIS inhibitor to the subject, wherein the CIS inhibitor competitively inhibits binding of CIS to JAK1 and/or JAK3.
2. The method of claim 1 , wherein JAK1 is phosphorylated JAK1 and/or JAK3 is phosphorylated JAK3.
3. The method of claim 2 , wherein phosphorylated JAK1 is phosphorylated at Tyr1034 and/or phosphorylated JAK3 is phosphorylated at Tyr980.
4. The method of claim 1 , wherein the CIS inhibitor competitively inhibits binding of CIS to IL-2Rβ phosphorylated at one or more of Tyr355, Tyr361 and Tyr392 and/or competitively inhibits binding of CIS to one or more of Elongin B, Elongin C or Cullin-5.
5. The method of claim 1 , further comprising administering one or more of IL-15, an IL-15 agonist, a B Raf protein kinase inhibitor, a MEK protein kinase inhibitor, or an immunotherapeutic agent to the subject.
6. The method of claim 1 , wherein the subject is suffering from a cancer or an infection, or is determined to be at risk of suffering from cancer or an infection.