MICB (MHC Class I Polypeptide-Related Sequence B)

We demonstrated the successful expression of Anti-MICB-CAR in NK cells, which enhances the anti-tumor activity of NK cells both in vitro and in vivo. This stress ligand-targeting approach provides a promising strategy for solid tumors.

Their downregulation attenuates NK cell function, promoting cervical cancer cell proliferation and survival via the Toll signaling pathway. These findings highlight the potential of targeting MICA/B-NK cell interactions as a therapeutic strategy for cervical cancer.

In vivo studies using an NSG mouse model demonstrate robust activation of patient-derived T and NK cells, leading to potent anti-MM effects. This work presents a dual-pronged immunotherapeutic strategy to overcome immune suppression in MM, offering a synergistic approach to harness both adaptive and innate immunity for enhanced cancer immunotherapy.

We summarize current strategies to mitigate immune barriers, discuss practical manufacturing challenges, and analyze available clinical data on NKG2D CAR-T trials. Collectively, these insights underscore both the promise and the hurdles of developing safe, universal, and scalable allogeneic CAR-T therapies for solid malignancies.

CYAD-02 presented an higher engraftment and an improved clinical activity (17% objective response rate) compared to CYAD-01 (no objective response). Altogether, our data provide proof of principle that knock-down of MICA/B can enhance CAR T-cell persistence and efficacy while maintaining a good safety profile.

Mechanistically, mbIL2 mitigated activation-induced apoptosis and suppressed exhaustion during tumor engagement, thereby sustaining NK cell viability. These findings establish mbIL2 as a critical enhancer of CAR-NK cell persistence and antitumor function, offering a clinically translatable strategy to overcome the limitations of cytokine-dependent therapies.

The chemotherapy drug called Adriamycin, often known as doxorubicin (Dox), is used to treat BC, including late stages. ABCG2 mRNA expression is markedly upregulated in MCF7 cells upon P53 and ERK5 downregulation. Collectively, these findings showed that DCA increases the susceptibility of breast cancer cells to Dox through the upregulation of NKG2DL and the downregulation of ABCG2 expression via a p53-ERK5 dependent pathway.

Stimulation with IL-2 and IL-15 or TGFβ1 altered PB-NK markers and stimulated their differentiation into ILC1-like cells in 3D models. These findings underscore the regulatory function of CAFs in shaping the response of the tumor microenvironment to immunotherapeutic interventions.

Mechanistically, IL-1β, IL-6, and TNF-α enhanced the transcription of MICA/B and PD-L1 genes via the PI3K/AKT, JAK/STAT3, and MKK/p38 MAPK pathways. Pro-inflammatory cytokines upregulated the expression of MICA/B and PD-L1, thereby promoting the cytotoxicity of CIK cells against MM by strengthening the NKG2D pathway, while PD-L1 blockade enhanced the cytotoxicity of CIK cells.

CLN-619 inhibited the shedding of MICA/B to effectively restore cytotoxic signaling pathways in immune cells. Potent antitumor activity of CLN-619 as a monotherapy was observed in several preclinical models. Activity of CLN-619 required a functional Fcγ1 domain, suggesting the requirement of simultaneous engagement of NKG2D and cluster of differentiation 16A (CD16A) on immune cells for optimal cytotoxicity. The preclinical data reported here support the assessment of CLN-619 in patients with cancer.

The three NK-activating receptor ligands were higher in the sera of the MASH group than those of the MASL group and strongly correlated with tumor markers, indicating the potential for hepatocarcinogenesis. Higher concentrations of serum B7H6 were correlated with advanced fibrosis and the degree of portal inflammation, which is a potential biomarker for predicting the pathogenesis of MASH.

Enhanced NK cell-mediated cytotoxicity was correlated with expression of NKG2D ligands (P<0.05). In conclusion, sesamin can induce cell cycle arrest and upregulate the expression of NKG2D ligands in MG-63 cells, thereby enhancing NK cell-mediated cytotoxicity against osteosarcoma cells.