cd38 inhibitor  (MedChemExpress)

Journal: Cell Reports Medicine

Article Title: Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants

doi: 10.1016/j.xcrm.2025.102210

Figure Lengend Snippet: CD38 + CD8 + TILs predict ICB resistance (A–H) scRNA-seq of CD45 + immune cells from melanoma patients. (A) CD8 + T cell clusters ( n = 6,350). (B–D) Expression of (B) CD38 , (C) PD-1 ( PDCD1 ), and (D) TCF7 . (E) CD8 + T cell clusters by ICB response, (F) Proportion of CD38 expressing CD8 + T cells in ICB responders (ICB-R) and non-responders (ICB-NR). Two-sided unpaired t test. Means (bars) and individual values (open circles) are shown. (G and H) Receiver-operating characteristic (ROC) curves, demonstrating (G) the predictive power of CD38 + CD8 + TILs in melanoma tumors and (H) the specific performance of cluster 6 exhausted CD8 + T cells for ICB resistance. FPR, false-positive rate; TPR, true-positive rate. (I–L) scRNA-seq analysis of CD8 T cells from melanoma validation cohort. (I) Uniform manifold approximation and projection (UMAP) of CD8 T cells ( n = 20,210). (J) Proportion of CD38 expressing CD8 + T cells. Two-sided unpaired t test. Means (bars) and individual values (open circles) are shown. (K) CD38 expression and (L) TCF7 expression. (M) Proportion of CD38 expressing CD8 + T cells from NSCLC (MPR, major pathological response; ICB-R, n = 23, non-MPR; ICB-NR, n = 34, two-sided unpaired t test). Means (bars) and individual values (open circles) are shown. (N) ROC curve demonstrating the predictive power of CD38 + CD8 + T cells for lack of ICB treatment benefit in NSCLC. See also and ; .

Article Snippet: When indicated, cells were treated with CD38 inhibitor 1 μM 78c (6391, Tocris), IFNβ (Peprotech, 300-02BC), JAK inhibitor 1 μM ruxolitinib (MCE, HY-50858), nicotinamide riboside chloride (NR) at 100 or 500 μM (Sigma-Aldrich, SMB00907-50MG), or 1 nM of FK866 NAMPT inhibitor (Tocris, 4808).

Techniques: Expressing, Biomarker Discovery

Journal: Cell Reports Medicine

Article Title: Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants

doi: 10.1016/j.xcrm.2025.102210

Figure Lengend Snippet: Intratumoral CD38 + CD8 + T cells accumulate during tumor progression (A) scRNA-seq of T/NK cells from B16 tumors (Tum), tumor-draining lymph nodes (dLN), and normal lymph nodes (nLN). (B and C) Dotplots indicating (B) Cd38 expression and (C) Cd38 and Tcf7 expression at days 7, 10, and 16. (D–G) CyTOF analysis of CD38 + CD8 + T cells in peripheral blood from melanoma patients (D) by response to ICB; before (E) and after (F) ICB treatment. (G) CD8 + CD38 + IgG4 + by response to ICB. Two-sided unpaired t test. Means (bars) and individual values (open circles) are shown. (H–M) scRNA-seq of T/NK tumor-infiltrating leukocytes from control/IgG ( n = 3) and αPD-1 ( n = 4) B16-ova tumors. (H) UMAP of T/NK cell clusters by condition; (I and J) Cd38 expression and (K) proportion of Cd38 expressing terminal effector CD8 + TILs per condition. Two-sided unpaired t test. Median (line) and individual values (open circles) are shown. (L and M) UMAP and track plots showing Cd38 gene expression. Immune population statistics can be found in D. ∗ p < 0.05. See also and .

Article Snippet: When indicated, cells were treated with CD38 inhibitor 1 μM 78c (6391, Tocris), IFNβ (Peprotech, 300-02BC), JAK inhibitor 1 μM ruxolitinib (MCE, HY-50858), nicotinamide riboside chloride (NR) at 100 or 500 μM (Sigma-Aldrich, SMB00907-50MG), or 1 nM of FK866 NAMPT inhibitor (Tocris, 4808).

Techniques: Expressing, Control, Gene Expression

Journal: Cell Reports Medicine

Article Title: Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants

doi: 10.1016/j.xcrm.2025.102210

Figure Lengend Snippet: CD38 hi CD8 + T cells are dysfunctional (A) Expression of exhaustion and effector/memory-related genes in CD8 + TILs from human melanoma tumors. (B) Co-expression deviation proportion plot demonstrating co-expression of exhaustion-related genes and TCF7 from melanoma validation cohort. (C and D) differentially expressed genes based on CD38 expression in (C) CD8 + TILs from human melanoma and (D) CD3 + TILs from B16-ova murine melanoma. (E and F) CD38 hi and CD38 lo B7-H3.CAR-T cells (E) surface staining of PD-1 + CD39 + TIM-3 + ( n = 3; two-sided paired t test) and (F) TCF7 expression ( n = 3; two-sided unpaired t test). Means (bars) and individual values (open circles) are shown. (G) Scheme depicting acute and chronic TCR stimulation. (H–J) (H) Acute and chronic B7-H3.CAR-T proliferation assay ( n = 3; two-way ANOVA with Sidak correction for multiple comparisons). Means ± SEM (shaded area) are shown. Staining of (I) CD38 + CD39 + and (J) PD-1 + TIM-3 + ( n = 3, two-sided paired t test). Means (bars) and individual values (open circles) are shown. (K) Cytotoxicity assay toward 10164 patient-derived melanoma cell line. A representative experiment out of three is presented; two more are in E and S4F. ( n = 3 biological replicates; three independent experiments; two-way ANOVA with Sidak correction for multiple comparisons). Means ± SEM (shaded area) are shown. (L–N) Analysis of chronically stimulated control sgRNA and CD38 sgRNA B7-H3.CAR-T cells. (L) Proliferation assay ( n = 3 biological replicates; three independent experiments; two-way ANOVA with Sidak correction for multiple comparisons). Means ± SEM (shaded area) are shown. (M) TCF7 intracellular staining ( n = 4; two-sided paired t test). Means (bars) and individual values (open circles) are shown. (N) Cytotoxicity assay against 10164 melanoma cells ( n = 3 biological replicates; three independent experiments; two-way ANOVA with Sidak correction for multiple comparisons). Means ± SEM (shaded area) are shown. ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗∗ p < 0.0001. See also ; and .

Article Snippet: When indicated, cells were treated with CD38 inhibitor 1 μM 78c (6391, Tocris), IFNβ (Peprotech, 300-02BC), JAK inhibitor 1 μM ruxolitinib (MCE, HY-50858), nicotinamide riboside chloride (NR) at 100 or 500 μM (Sigma-Aldrich, SMB00907-50MG), or 1 nM of FK866 NAMPT inhibitor (Tocris, 4808).

Techniques: Expressing, Biomarker Discovery, Staining, Proliferation Assay, Cytotoxicity Assay, Derivative Assay, Control

Journal: Cell Reports Medicine

Article Title: Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants

doi: 10.1016/j.xcrm.2025.102210

Figure Lengend Snippet: CD38 + T cells exhibit altered bioenergetics (A) Correlation analysis between the GSEA of CD38 +/− CD8 + T cells in human melanoma and CD38 +/− CD3 + T cells in B16-ova murine melanoma. (B–E) Flow cytometry of (B and D) mitochondrial mass and (C and E) MMP in indicated groups ( n = 3; two-sided paired t test). Means (bars) and individual values (open circles) are shown. (F) Oxygen consumption rate (OCR) under basal condition and in response to inhibitors ( n = 5, two biological replicates, two-way ANOVA with Sidak correction for multiple comparisons). Data are presented as mean ± SEM. (G and H) Relative levels of (G) NAD + (nicotinamide adenine dinucleotide) and (H) NADP + (nicotinamide adenine dinucleotide phosphate); log 2 fold change (L2FC) from control is shown ( n = 6 biological replicates; two independent experiments; two-sided unpaired t test). Means (bars) and individual values (open circles) are shown. (I) scheme of NAD + metabolism and L2FC of indicated analytes. (J) OCR as in (F) of B7-H3.CAR-T cells ± CD38i ( n = 5, two biological replicates, two-way ANOVA with Sidak correction for multiple comparisons). Data are presented as mean ± SEM. (K and L) staining of (K) TIM-3 + PD-1 + and (L) CD39 + TIM-3 + in B7-H3.CAR-T ± CD38i ( n ≥ 4; two-sided paired t test). Means (bars) and individual values (open circles) are shown. (M) TCF7 expression by RT-qPCR in B7-H3.CAR-T cells in indicated groups ( n = 4; two-sided unpaired t test). Means (bars) and individual values (open circles) are shown. (N and O) Relative levels of (N) NAM (nicotinamide) and (O) ADPR (adenosine diphosphate ribose) in B7-H3.CAR-T cells ± CD38i ( n = 6 biological replicates; two independent experiments; two-sided unpaired t test). Means (bars) and individual values (open circles) are shown. ∗ p < 0.05, ∗∗ p < 0.01. See also ; , , and .

Article Snippet: When indicated, cells were treated with CD38 inhibitor 1 μM 78c (6391, Tocris), IFNβ (Peprotech, 300-02BC), JAK inhibitor 1 μM ruxolitinib (MCE, HY-50858), nicotinamide riboside chloride (NR) at 100 or 500 μM (Sigma-Aldrich, SMB00907-50MG), or 1 nM of FK866 NAMPT inhibitor (Tocris, 4808).

Techniques: Flow Cytometry, Control, Staining, Expressing, Quantitative RT-PCR

Journal: Cell Reports Medicine

Article Title: Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants

doi: 10.1016/j.xcrm.2025.102210

Figure Lengend Snippet: Type I interferon induces CD38 expression in T cells (A and B) Expression of type I IFN-stimulated genes in CD8 + TILs from human melanoma (A) by cluster and (B) by response to ICB. (C–E) Staining of CD38 in human CD8 + TILs ( n = 3; in C, two-sided paired t test; in E, two-way ANOVA with Sidak correction for multiple comparisons). Means (bars) and individual values (open circles) are shown. (F) Analysis of relative NAD(H) in control or IFN-β-treated CD8 + TILs ( n = 3; two-sided unpaired t test). Means (bars) and individual values (open circles) are shown. (G and H) staining of TIM-3 in CD8 + TILs in indicated groups ( n > 4; two-sided paired t test). (I and J) Flow-cytometry analysis of (I) MMP and (J) mitochondrial mass of CD8 + TILs ± IFN-β ( n = 3; two-sided unpaired t test). Means (bars) and individual values (open circles) are shown. ∗ p < 0.05; ns, not significant. See also .

Article Snippet: When indicated, cells were treated with CD38 inhibitor 1 μM 78c (6391, Tocris), IFNβ (Peprotech, 300-02BC), JAK inhibitor 1 μM ruxolitinib (MCE, HY-50858), nicotinamide riboside chloride (NR) at 100 or 500 μM (Sigma-Aldrich, SMB00907-50MG), or 1 nM of FK866 NAMPT inhibitor (Tocris, 4808).

Techniques: Expressing, Staining, Control, Flow Cytometry

Journal: Cell Reports Medicine

Article Title: Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants

doi: 10.1016/j.xcrm.2025.102210

Figure Lengend Snippet: CD38 blockade overcomes ICB resistance (A) Scheme of PDOTS preparation. (B) Viability assessment of melanoma PDOTS ( n = 27) following treatment with anti-PD-1 (pembrolizumab), anti-CD38 (daratumumab), or the combination. Individual values (open circles) indicate the mean for each PDOTS specimen; one-way ANOVA with Greenhouse-Geisser correction for multiple comparisons. (C) Waterfall plot of melanoma PDOTS ( n = 27). Response is defined as a 30% reduction from control (lower dashed lines); growth is defined as a 20% increase from control (upper dashed lines). Viability percentages of controls are in . (D and E) PDOTS viability assessment with indicated treatments ( n = 3 biological replicates per PDOTS specimen, one-way ANOVA with Tukey correction for multiple comparisons). Means (bars) and individual values (open circles) are shown. (F) Representative images of PDOTS in (E). HO, Hoechst (blue); PI, propidium iodide (dead cells [red]). Scale bars, 100 μm. (G) scRNA-seq analysis of CD8 + T cells ( n = 39,621) from tumors in (B) and (C) ( n = 21), showing CD38 expression. (H) CD38 expression in indicated clusters ( n = 21, one-way ANOVA with Tukey correction for multiple comparisons). (I) GSEA of CD38 + PD-1 blockade responding tumors in Prolif.CD8 and CXCL13 + T cell clusters ( n = 12). (J) Module score of IFNG and GZMA in Prolif.CD8 and CXCL13 + T cells discriminate PDOTS responsive (R) and non-responsive (NR) to dual PD-1/CD38 blockade (R, n = 12; NR, n = 8; individual graphs are in H and S11I). (K and L) Viability assessment of (K) B16-ova MDOTS ( n = 6 biological replicates, two independent experiments) and (L) CT26-GFP MDOTS treated with indicated treatments ( n = 12 biological replicates, four independent experiments, one-way ANOVA with Tukey correction for multiple comparisons). Means (bars) and individual values (open circles) are shown. ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001, ∗∗∗∗ p < 0.0001; ns, not significant. See also ; , , , and .

Article Snippet: When indicated, cells were treated with CD38 inhibitor 1 μM 78c (6391, Tocris), IFNβ (Peprotech, 300-02BC), JAK inhibitor 1 μM ruxolitinib (MCE, HY-50858), nicotinamide riboside chloride (NR) at 100 or 500 μM (Sigma-Aldrich, SMB00907-50MG), or 1 nM of FK866 NAMPT inhibitor (Tocris, 4808).

Techniques: Control, Expressing

Journal: Cell Reports Medicine

Article Title: Overcoming resistance to immunotherapy by targeting CD38 in human tumor explants

doi: 10.1016/j.xcrm.2025.102210

Figure Lengend Snippet: Disrupting CD38 restores NAD + and overcomes ICB resistance (A and B) Viability assessment of (A) B16-ova MDOTS ( n = 6 biological replicates, two independent experiments) and (B) CT26-GFP MDOTS ( n = 12 biological replicates, four independent experiments). One-way ANOVA with Tukey correction for multiple comparisons. Means (bars) and individual values (open circles) are shown. (C) Representative images of MDOTS in (B). HO, Hoechst (blue); PI, propidium iodide (dead cells [red]); tumor, GFP-tumor cells. (D) Viability assessment of CT26-GFP MDOTS with indicated treatments ( n = 6 biological replicates, two independent experiments, one-way ANOVA with Tukey correction for multiple comparisons). Means (bars) and individual values (open circles) are shown. (E) Viability assessment of melanoma PDOTS with indicated treatments. ( n = 18, six independent specimens; mixed-effects one-way ANOVA with Tukey correction for multiple comparisons). (F) Viability assessment of melanoma PDOTS treated with indicated treatments ( n = 3 biological replicates; one-way ANOVA with Tukey correction for multiple comparisons). Means (bars) and individual values (open circles) are shown. (G) Scheme demonstrating the effect of targeting CD38 in T cells by increasing NAD + and TCF7 expression along with restoring mitochondrial function and overcoming resistance to ICB. ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001, ∗∗∗∗ p < 0.0001; ns, not significant. See also and .

Article Snippet: When indicated, cells were treated with CD38 inhibitor 1 μM 78c (6391, Tocris), IFNβ (Peprotech, 300-02BC), JAK inhibitor 1 μM ruxolitinib (MCE, HY-50858), nicotinamide riboside chloride (NR) at 100 or 500 μM (Sigma-Aldrich, SMB00907-50MG), or 1 nM of FK866 NAMPT inhibitor (Tocris, 4808).

Techniques: Expressing

Journal: Aging Cell

Article Title: SIRT2 and NAD + Boosting Broadly Suppress Aging‐Associated Inflammation

doi: 10.1111/acel.70162

Figure Lengend Snippet: 78c suppresses aging‐associated inflammation and tissue function decline. Comparison of aged (24 months old) WT mice treated with or without 78c for 2 months. (A–C), Quantitative real‐time PCR analyses for the mRNA levels of the indicated genes in the GA (A, n = 7,6), the liver (B, n = 6) and the hippocampus (C, n = 7). (D–G), Immunostaining for CD68+ cells and quantification of the GA (D, E, n = 7) and the liver (F, G, n = 7,6) sections. Scale bar: 50 μm. 5 images examined from 3 slides/mouse. (H, I), Immunostaining for phosphorylated STING and quantification of the GA sections. Scale bar: 30 μm. n = 7.4 images examined from 3 slides/mouse. (J, K), Western blotting analyses and quantification of TBK1 and phosphorylated TBK1 in the liver. GAPDH was used as a control. n = 3. (L, M), Levels of TNF‐α and IL‐6 in the serum. n = 6. (N), Latency to fall in the grip strength test. n = 10. (O), Time spent in the target quadrant in the Barnes maze test. n = 10, 9. Data are mean ± s.e.m. * p < 0.05. ** p < 0.01. *** p < 0.001. Student's t test.

Article Snippet: 78c (MedChemExpress LLC, #HY‐123999) was administered to mice by intraperitoneal injection (10 mg/kg/dose) twice daily.

Techniques: Comparison, Real-time Polymerase Chain Reaction, Immunostaining, Western Blot, Control

Journal: Journal of Neuroinflammation

Article Title: Targeting SARM1 as a novel neuroprotective therapy in neurotropic viral infections

doi: 10.1186/s12974-025-03423-5

Figure Lengend Snippet: Neurotropic virus infections of mouse cortical neurons induce SARM1 activation and increased production of cADPR. ( A - C ) Survival curves, weight loss and clinical scores of infected C57BL/6 mice were measured from day 0 until the end of the infection. Intracranial infections with JEV, HSV-1, RABV or mock (PBS) was performed in C57BL/6 mice ( n = 6 for each mock-infected; n = 18 for each neurotropic virus infection group), respectively. Neurological disease evaluation included mortality ( A ), mean daily body weight loss ( B ), and clinical scores ( C ). The mock infection mice did not have any symptoms. The scores of disease severity or 30% loss of initial body weight were used as termination criteria. ( D - F ) The immunoblot analysis of SARM1, NMNAT2, and viral proteins in whole-cell lysates from the mouse cortex was conducted at the indicated time points following mock, JEV ( D ), HSV-1 ( E ), and RABV ( F ) infections using GAPDH as an internal control. ( G ) Representative micrographs of immunohistochemistry of brain sections stained for SARM1 from mock-, JEV (5dpi)-, HSV-1 (5dpi)-, or RABV (8dpi)-infected mice. ( H and I ) Mice were mock-infected or infected with neurotropic viruses at the indicated time points, respectively; the NAD + ( H ) and cADPR ( I ) levels were tested in the mouse cortex, quantified as the ratio of (NAD + or cADPR concentration) / (NAD + or cADPR concentration of mock infected group) × 100%. ( J ) The day before neurotropic virus infection, mice were orally given vehicle or CD38 inhibitor 1 (twice daily). Compared with the mock-infected group, the levels of NAD + and cADPR in the cortex of mice were detected after JEV (5dpi), HSV-1 (5dpi), and RABV (8dpi) infection, respectively. Individual data points are shown ( n = 12 for each group). Data are expressed as means ± SEM, Student’s t test, * P <0.05, ** P <0.01,*** P <0.001

Article Snippet: The CD38 inhibitor 1 and FK866 were procured from Selleck (catalog numbers T14913 and T2644, respectively).

Techniques: Virus, Activation Assay, Infection, Western Blot, Control, Immunohistochemistry, Staining, Concentration Assay