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1.
Biomedicines ; 12(1)2024 Jan 16.
Article in English | MEDLINE | ID: mdl-38255301

ABSTRACT

NKG2D is an activating receptor expressed by all human NK cells and CD8 T cells. Harnessing the NKG2D/NKG2D ligand axis has emerged as a viable avenue for cancer immunotherapy. However, there is a long-standing controversy over whether soluble NKG2D ligands are immunosuppressive or immunostimulatory, originating from conflicting data generated from different scopes of pre-clinical investigations. Using multiple pre-clinical tumor models, we demonstrated that the impact of the most characterized human solid tumor-associated soluble NKG2D ligand, the soluble MHC I chain-related molecule (sMIC), on tumorigenesis depended on the tumor model being studied and whether the tumor cells possessed stemness-like properties. We demonstrated that the potential of tumor formation or establishment depended upon tumor cell stem-like properties irrespective of tumor cells secreting the soluble NKG2D ligand sMIC. Specifically, tumor formation was delayed or failed if sMIC-expressing tumor cells expressed low stem-cell markers; tumor formation was rapid if sMIC-expressing tumor cells expressed high stem-like cell markers. However, once tumors were formed, overexpression of sMIC unequivocally suppressed tumoral NK and CD8 T cell immunity and facilitated tumor growth. Our study distinguished the differential impacts of soluble NKG2D ligands in tumor formation and tumor progression, cleared the outstanding controversy over soluble NKG2D ligands in modulating tumor immunity, and re-enforced the viability of targeting soluble NKG2D ligands for cancer immunotherapy for established tumors.

2.
ACS Cent Sci ; 9(6): 1070-1072, 2023 Jun 28.
Article in English | MEDLINE | ID: mdl-37396858
3.
ACS Cent Sci ; 9(6): 1073-1075, 2023 Jun 28.
Article in English | MEDLINE | ID: mdl-37396869
4.
Nature ; 2023 Mar 22.
Article in English | MEDLINE | ID: mdl-36949136
5.
Commun Biol ; 4(1): 905, 2021 07 22.
Article in English | MEDLINE | ID: mdl-34294876

ABSTRACT

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.


Subject(s)
Cellular Reprogramming , Inflammation/metabolism , Killer Cells, Natural/physiology , NK Cell Lectin-Like Receptor Subfamily K/genetics , Cell Line, Tumor , Humans , Ligands , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Phenotype
6.
J Hematol Oncol ; 13(1): 74, 2020 06 09.
Article in English | MEDLINE | ID: mdl-32517713

ABSTRACT

BACKGROUND: Melanoma patients who have detectable serum soluble NKG2D ligands either at the baseline or post-treatment of PD1/PDL1 blockade exhibit poor overall survival. Among families of soluble human NKG2D ligands, the soluble human MHC I chain-related molecule (sMIC) was found to be elevated in melanoma patients and mostly associated with poor response to PD1/PDL1 blockade therapy. METHODS: In this study, we aim to investigate whether co-targeting tumor-released sMIC enhances the therapeutic outcome of PD1/PDL1 blockade therapy for melanoma. We implanted sMIC-expressing B16F10 melanoma tumors into syngeneic host and evaluated therapeutic efficacy of anti-sMIC antibody and anti-PDL1 antibody combination therapy in comparison with monotherapy. We analyzed associated effector mechanism. We also assessed sMIC/MIC prevalence in metastatic human melanoma tumors. RESULTS: We found that the combination therapy of the anti-PDL1 antibody with an antibody targeting sMIC significantly improved animal survival as compared to monotherapies and that the effect of combination therapy depends significantly on NK cells. We show that combination therapy significantly increased IL-2Rα (CD25) on NK cells which sensitizes NK cells to low dose IL-2 for survival. We demonstrate that sMIC negatively reprograms gene expression related to NK cell homeostatic survival and proliferation and that antibody clearing sMIC reverses the effect of sMIC and reprograms NK cell for survival. We further show that sMIC/MIC is abundantly present in metastatic human melanoma tumors. CONCLUSIONS: Our findings provide a pre-clinical proof-of-concept and a new mechanistic understanding to underscore the significance of antibody targeting sMIC to improve therapeutic efficacy of anti-PD1/PDL1 antibody for MIC/sMIC+ metastatic melanoma patients.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Histocompatibility Antigens Class I/immunology , Immune Checkpoint Inhibitors/therapeutic use , Killer Cells, Natural/cytology , Melanoma, Experimental/drug therapy , NK Cell Lectin-Like Receptor Subfamily K/agonists , Neoplasm Proteins/antagonists & inhibitors , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Animals , Antineoplastic Agents, Immunological/pharmacology , CD8-Positive T-Lymphocytes/immunology , Cell Survival , Drug Synergism , Histocompatibility Antigens Class I/physiology , Homeostasis , Humans , Immune Checkpoint Inhibitors/pharmacology , Interleukin-2 Receptor alpha Subunit/biosynthesis , Interleukin-2 Receptor alpha Subunit/genetics , Ligands , Lung Neoplasms/prevention & control , Lung Neoplasms/secondary , Male , Melanoma, Experimental/immunology , Melanoma, Experimental/secondary , Mice , Mice, Transgenic , Neoplasm Proteins/physiology , Solubility , Specific Pathogen-Free Organisms , Transplantation, Isogeneic , Tumor Microenvironment , Up-Regulation
7.
J Clin Med ; 8(9)2019 Sep 19.
Article in English | MEDLINE | ID: mdl-31546818

ABSTRACT

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.

8.
J Immunother Cancer ; 7(1): 223, 2019 08 26.
Article in English | MEDLINE | ID: mdl-31446896

ABSTRACT

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.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , NK Cell Lectin-Like Receptor Subfamily K/immunology , Neoplasms/drug therapy , Programmed Cell Death 1 Receptor/immunology , Cell Line, Tumor , Humans , Ligands , Neoplasms/genetics
9.
Curr Opin Immunol ; 51: 55-61, 2018 04.
Article in English | MEDLINE | ID: mdl-29525346

ABSTRACT

NKG2D is an activating immune receptor expressed by NK and effector T cells. Induced expression of NKG2D ligand on tumor cell surface during oncogenic insults renders cancer cells susceptible to immune destruction. In advanced human cancers, tumor cells shed NKG2D ligand to produce an immune soluble form as a means of immune evasion. Soluble NKG2D ligands have been associated with poor clinical prognosis in cancer patients. Harnessing NKG2D pathway is considered a viable avenue in cancer immunotherapy over recent years. In this review, we will discuss the progress and perspectives.


Subject(s)
Disease Susceptibility/immunology , Lymphocyte Subsets/immunology , Lymphocyte Subsets/metabolism , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Neoplasms/immunology , Neoplasms/metabolism , Animals , Humans , Immune Evasion , Immunotherapy, Adoptive , Ligands , Neoplasms/genetics , Neoplasms/therapy , Protein Binding , Receptors, Antigen, T-Cell/metabolism , Signal Transduction
10.
Cell Metab ; 27(1): 85-100.e8, 2018 01 09.
Article in English | MEDLINE | ID: mdl-29129787

ABSTRACT

Heightened effector function and prolonged persistence, the key attributes of Th1 and Th17 cells, respectively, are key features of potent anti-tumor T cells. Here, we established ex vivo culture conditions to generate hybrid Th1/17 cells, which persisted long-term in vivo while maintaining their effector function. Using transcriptomics and metabolic profiling approaches, we showed that the enhanced anti-tumor property of Th1/17 cells was dependent on the increased NAD+-dependent activity of the histone deacetylase Sirt1. Pharmacological or genetic inhibition of Sirt1 activity impaired the anti-tumor potential of Th1/17 cells. Importantly, T cells with reduced surface expression of the NADase CD38 exhibited intrinsically higher NAD+, enhanced oxidative phosphorylation, higher glutaminolysis, and altered mitochondrial dynamics that vastly improved tumor control. Lastly, blocking CD38 expression improved tumor control even when using Th0 anti-tumor T cells. Thus, strategies targeting the CD38-NAD+ axis could increase the efficacy of anti-tumor adoptive T cell therapy.


Subject(s)
ADP-ribosyl Cyclase 1/metabolism , Immunotherapy , NAD/metabolism , Neoplasms/immunology , Neoplasms/therapy , T-Lymphocytes/immunology , Animals , Forkhead Box Protein O1/metabolism , Glutamine/metabolism , Mice, Inbred C57BL , Neoplasms/metabolism , Sirtuin 1/metabolism , Th1 Cells/immunology , Th17 Cells/immunology
11.
Nat Prod Res ; 30(12): 1455-8, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26212208

ABSTRACT

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, (1)H NMR, (13)C 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.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Sesterterpenes/pharmacology , Antineoplastic Agents, Phytogenic/isolation & purification , Apoptosis/drug effects , Ascomycota/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Chromatography, High Pressure Liquid , Drug Screening Assays, Antitumor , Endophytes/chemistry , Humans , Inhibitory Concentration 50 , Molecular Structure , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation/drug effects , Sesterterpenes/isolation & purification , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism
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