As part of our research on the control mechanisms of NK cell immunity, we focus mainly on the negative signaling cascades, and specifically on the phosphatase SHP-1, which inhibits NK immune cell function. This enzyme dephosphorylates signaling proteins responsible for NK effector activity. Studies in our laboratory identified novel substrates of SHP-1 in NK cells, which are required for balanced NK cell activity (Science Signaling 9: ra54.2016). Based on our data, we developed an innovative nanoparticle-based therapeutic approach, in which we silence key intrinsic inhibitory signaling regulators of NK cell responsiveness, subsequentially increasing NK cell killing capacity in the tumor microenvironment. This potential therapeutic approach overcomes the shortcomings of the current cell-based treatments used today.

Additional studies in our laboratory focus on the mechanisms that control SHP-1 regulation. We demonstrated that actin dynamics (actin retrograde flow (ARF)) controls the activity of SHP-1 by affecting its conformational state, and, thus, its phosphatase activity in the NK immunological synapse (NKIS) (EMBO J. 37(5), 2018). In addition, we showed that cytoskeletal proteins, including WASp and Myosin, regulate ARF, thereby affecting downstream SHP-1 activity and NK anti-tumor activity (Cancer 14(15):3756, 2022). We also identified a rapid molecular mechanism modulated via the kinase PKCθ, phosphorylation SHP-1 on its C’ terminus, inactivating this enzyme, and consequently enhancing NK cell immune function.

We study the role of the cytoskeleton on immune cell behavior and malignant cell fate. To facilitate their invasion of adjacent tissues and their continued proliferation, cancer cells depend on the specialized network of protein filaments that enable cell contraction, motility, and the organization and function of internal organelles. The cytoskeleton is comprised of actin filaments, microtubules, and intermediate filaments. Actin is the most abundant protein in most eukaryotic cells. These spherical protein subunits form filaments whose assembly is regulated by a multitude of proteins, which are collectively known as actin nucleation-promoting factors (NPFs). One such NPF, the Wiskott–Aldrich Syndrome protein (WASp), is critical in regulating cytoskeletal activity in hematopoietic cells. However, the role of WASp in promoting hematopoietic malignancies remained unclear. WASp is exclusively expressed in cells of the hematopoietic lineage, and is, therefore a potentially desirable therapeutic target. We performed screening of small molecule compounds (SMCs) that potentially bind WASp, promote its degradation in malignant hematopoietic cells, and may thereby suppress aggressive tumor phenotypes such as uncontrolled proliferation, migration, and invasion of adjacent healthy tissues. We identified a specific SMC that binds with high affinity to the open conformation of WASp dominantly expressed in malignant cells, leading to WASp degradation and inhibition of WAS-dependent activity both in vitro and in animal models. Using artificial intelligence tools and biophysical technologies, we attained a detailed model of the interaction between the SMC and its WASp target. Since this SMC demonstrated specificity and limited toxicity in animal models, it may potentially be optimized and harnessed as a future modality for the treatment of hematopoietic malignancies.