NEDD8-activating enzyme inhibition potentiates the anti-myeloma activity of natural killer cells.
Sara PetilloElena SprovieroLuisa LoconteLorenzo CuolloAlessandra ZingoniRosa MolfettaCinzia FiondaAlessandra SorianiCristina CerboniMaria Teresa PetrucciFrancesca FazioRossella PaoliniAngela SantoniMarco CippitelliPublished in: Cell death & disease (2023)
Natural Killer (NK) cells act as important regulators in the development and progression of hematological malignancies and their suppressor activity against Multiple Myeloma (MM) cells has been confirmed in many studies. Significant changes in the distribution of NK cell subsets and dysfunctions of NK cell effector activities were described in MM patients and correlated with disease staging. Thus, restoring or enhancing the functionality of these effectors for the treatment of MM represents a critical need. Neddylation is a post-translational modification that adds a ubiquitin-like molecule, NEDD8, to the substrate protein. One of the outcomes is the activation of the Cullin Ring Ligases (CRLs), a class of ubiquitin-ligases that controls the degradation of about 20% of proteasome-regulated proteins. Overactivation of CRLs has been described in cancer and can lead to tumor growth and progression. Thus, targeting neddylation represents an attractive approach for cancer treatment. Our group has recently described how pharmacologic inhibition of neddylation increases the expression of the NKG2D activating receptor ligands, MICA and MICB, in MM cells, making these cells more susceptible to NK cell degranulation and killing. Here, we extended our investigation to the direct role of neddylation on NK cell effector functions exerted against MM. We observed that inhibition of neddylation enhanced NK cell-mediated degranulation and killing against MM cells and improved Daratumumab/Elotuzumab-mediated response. Mechanistically, inhibition of neddylation increased the expression of Rac1 and RhoA GTPases in NK cells, critical mediators for an efficient degranulation at the immunological synapse of cytotoxic lymphocytes, and augmented the levels of F-actin and perforin polarization in NK cells contacting target cells. Moreover, inhibition of neddylation partially abrogated TGFβ-mediated repression of NK cell effector activity. This study describes the role of neddylation on NK cell effector functions and highlights the positive immunomodulatory effects achieved by the inhibition of this pathway in MM.
Keyphrases
- nk cells
- induced apoptosis
- cell cycle arrest
- multiple myeloma
- signaling pathway
- newly diagnosed
- oxidative stress
- cell death
- type diabetes
- immune response
- type iii
- transcription factor
- squamous cell carcinoma
- metabolic syndrome
- long non coding rna
- binding protein
- skeletal muscle
- ejection fraction
- peripheral blood
- cell migration
- pet ct
- chronic kidney disease
- squamous cell