The present work describes the anticancer activity of Ophiobolin A isolated from the endophytic fungus Bipolaris setariae. Ophiobolin A was isolated using preparative HPLC and its structure was confirmed by HRMS, ¹H NMR, ¹³C NMR, COSY, DEPT, HSQC and HMBC. It inhibited solid and haematological cancer cell proliferation with IC₅₀ of 0.4–4.3 μM. In comparison, IC₅₀ against normal cells was 20.9 μM. It was found to inhibit the phosphorylation of S6 (IC₅₀ = 1.9 ± 0.2 μM), ERK (IC₅₀ = 0.28 ± 0.02 μM) and RB (IC₅₀ = 1.42 ± 0.1 μM), the effector proteins of PI3K/mTOR, Ras/Raf/ERK and CDK/RB pathways, respectively. It induced apoptosis and inhibited cell cycle progression in MDA-MB-231 cancer cells with concomitant inhibition of signalling proteins. Thus, this study reveals that anticancer activity of Ophiobolin A is associated with simultaneous inhibition of multiple oncogenic signalling pathways namely PI3K/mTOR, Ras/Raf/ERK and CDK/RB.

Background Insufficient co-stimulation accounts for a great deal of the suboptimal activation of cytotoxic CD8 T cells (CTLs) and presumably unsatisfactory clinical expectation of PD1/PD-L1 therapy. Tumor-derived soluble NKG2D ligands are associated with poor clinical response to PD1/PD-L1 blockade therapy in cancer patients. One of the mostly occurring tumor-derived soluble NKG2D ligands, the soluble MHC I chain related molecule (sMIC) can impair co-stimulation to CD8 T cells. We investigated whether co-targeting sMIC can provide optimal co-stimulation to CTLs and enhance the therapeutic effect of PD1/PD-L1 blockades. Methods Single agent therapy of a PD1/PD-L1 blockade antibody or a sMIC-targeting non-blocking antibody or a combination therapy of the two antibodies were implied to well-characterized pre-clinical MIC/sMIC⁺ tumor models that closely resemble the NKG2D-mediated oncoimmune dynamics of MIC⁺ cancer patients. Therapeutic efficacy and associated effector mechanisms were evaluated. Results We show that antibody co-targeting sMIC enables or enhances the response of sMIC⁺ tumors to PD1/PD-L1 blockade therapy. The therapy response of the combination therapy was associated with enhanced antigen-specific CD8 T cell enrichment and function in tumors. We show that co-targeting sMIC with a nonblocking antibody provides antigen-specific CD8 T cells with NKG2D and CD28 dual co-stimulation, in addition to elimination of inhibitory signals, and thus amplifies antigen-specific CD8 T cell anti-tumor responses. Conclusion Our findings provide the proof-of-concept rationale and previously undiscovered mechanisms for co-targeting sMIC to enable and enhance the response to PD1/PD-L1 blockade therapy in sMIC⁺ cancer patients.

Natural killer (NK) cells are critical immune components in controlling tumor growth and dissemination. Given their innate capacity to eliminate tumor cells without prior sensitization, NK-based therapies for cancer are actively pursued pre-clinically and clinically. However, recent data suggest that tumors could induce functional alterations in NK cells, polarizing them to tumor-promoting phenotypes. The potential functional plasticity of NK cells in the context of tumors could lead to undesirable outcomes of NK-cell based therapies. In this review, we will summarize to-date evidence of tumor-associated NK cell plasticity and provide our insights for future investigations and therapy development.

Natural Killer (NK) cell dysfunction is associated with poorer clinical outcome in cancer patients. What regulates NK cell dysfunction in tumor microenvironment is not well understood. Here, we demonstrate that the human tumor-derived NKG2D ligand soluble MIC (sMIC) reprograms NK cell to secrete pro-tumorigenic cytokines with diminished cytotoxicity and polyfunctional potential. Antibody clearing sMIC restores NK cell to a normal cytotoxic effector functional state. We discovered that sMIC selectively activates the CBM-signalosome inflammatory pathways in NK cells. Conversely, tumor cell membrane-bound MIC (mMIC) stimulates NK cell cytotoxicity through activating PLC2γ2/SLP-76/Vav1 pathway. Ultimately, antibody targeting sMIC effectuated the in vivo anti-tumor effect of adoptively transferred NK cells. Our findings uncover an unrecognized mechanism that could instruct NK cell to a dysfunctional state in response to cues in the tumor microenvironment. Our findings provide a rationale for co-targeting sMIC to enhance the efficacy of the ongoing NK cell-based cancer immunotherapy.