No abstract

The transcription factor NF-KB is sequestered in the cytoplasm by the inhibitor protein IKBc~. Extracellular inducers of NF-KB activate signal transduction pathways that result in the phosphorylation and subsequent degradation of IKBa. At present, the link between phosphorylation of IKB~x and its degradation is not understood. In this report we provide evidence that phosphorylation of serine residues 32 and 36 of IKBcx targets the protein to the ubiquitin-proteasome pathway. IKBa is ubiquitinated in vivo and in vitro following phosphorylation, and mutations that abolish phosphorylation and degradation of IKBa in vivo prevent ubiquitination in vitro. Ubiquitinated IgBa remains associated with NF-KB, and the bound IKBa is degraded by the 26S proteasome. Thus, ubiquitination provides a mechanistic link between phosphorylation and degradation of IKBr

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We have shown that thalidomide (Thal) and its immunomodulatory derivatives (IMiDs), proteasome inhibitor PS-341, and As 2 O 3 act directly on multiple myeloma (MM) cells and in the bone marrow (BM) milieu to overcome drug resistance. Although Thal/IMiDs, PS-341, and

Recent clinical trials using immunotherapy demonstrate its potential to control cancer by disinhibiting the immune system. Immune checkpoint blocking (ICB) antibodies such as anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) or anti-Programmed cell death protein 1/anti-Programmed death-ligand 1 (anti-PD-1/anti-PD-L1)1 have demonstrated durable clinical responses in various cancers. Although these new immunotherapies have significant impact on cancer treatment, multiple mechanisms of immune resistance exist in tumors. Among the key mechanisms, myeloid cells play a major role in limiting effective tumor immunity. 2–4 Growing evidence suggests that high infiltration of immune-suppressive myeloid cells correlates with poor prognosis and ICB resistance. 5,6 These observations suggest a need for a precision medicine approach where the design of the immunotherapeutic combinations are tailored based on tumor immune landscape to overcome such resistance mechanisms. Herein we employ a preclinical model system and show that resistance to ICB is directly mediated by the suppressive activity of infiltrating myeloid cells in various tumors. Furthermore, selective pharmacologic targeting of the gamma isoform of phosphoinositide 3-kinase (PI3K-γ), highly expressed in myeloid cells, restores sensitivity to ICB. We demonstrate that targeting PI3K–γ, with a selective inhibitor, currently being evaluated in a phase 1 clinical trial (NCT02637531), can reshape the tumor immune microenvironment and promote cytotoxic T cell-mediated tumor regression without targeting cancer cells directly. Our results introduce opportunities for new combination strategies using a selective small molecule PI3K-γ inhibitor, such as IPI-549, to overcome resistance to ICB in patients with high levels of suppressive myeloid cell infiltration in tumors.