## 2 Results
### MYC Downregulation Improves the Activation State of T-Cells Engaged by Blinatumomb  
We next evaluated whether lymphoma-intrinsic MYC could suppress the activity of effector T-cells by comparing their cytokine release after T-cell engager blinatumomb-mediated cytotoxicity against parental OCI-LY18 WT versus MYC downregulated cells. The increased blinatumomb-mediated cytotoxicity of MYC downregulated clones was accompanied by significantly higher levels of IL-2, IFN-\(\gamma\), IL-10 and TNF-\(\alpha\) secretion (Figure 4B). The Granzyme B, IL-6 and IL-4 secretion was also higher in some of the clones (Figure 4C). Overall, the increased cytokine secretion confirmed that MYC overexpression had a suppressive impact on effector T-cells. Additionally, we investigated the tumor cell surface expression of molecules involved in T cell-mediated cytotoxicity. Although the expression of HVEM and galectin-9 was increased in MYC downregulated clones (Figure S4A), CD155 (ligand of TIGIT) was decreased, and the expression of adhesion and costtimulatory molecules CD58 and CD80 was increased (Figure S4B). These findings point towards the suppression of T-cell activation as a third mechanism of MYC-mediated escape from T cell-based immunotherapeutic approaches. MYC Inhibition by Synthetic MYC Inhibitor 10058-F4 Boosts Antibody Therapy in B-Cell Alignancies Despite Tumor Heterogeneity  
Finally, we evaluated primary tumor cell samples directly obtained from DLBCL and MM patients using the synthetic MYC inhibitor 10058-F4. These lymph node and bone marrow samples also contained the necessary immune effector cells. Therefore, to mitigate the toxic effects of 10058-F4 on T-cells and NK-cells, we directly added 10058-F4 to the assay for a shorter time period (16 h) at concentrations that were non-toxic for NK-cells (12.5-50 \(\upmu\)M, Figure 5A). As a single agent, 10058-F4 induced moderate cytotoxicity in DLBCL and MM cells at these concentrations (Figure 5B). Rituximab- and daratumumab-mediated cytotoxicity was moderate to good (Figure 5C). The combination of 10058-F4 (25 \(\upmu\)M) with rituximab or daratumumab (100 ng/mL) showed synergism in 7/15 samples (Figure 5D), indicating the possibility to improve the efficacy of immunotherapeutic approaches in primary B-cell malignancies through MYC inhibition. Figure 5: Combination of MYC inhibitor 10058-F4 with conventional therapeutic antibodies increases tumor cell kill in DLBCL and MM tumor samples. (**A**) Peripheral blood mononuclear cells from n = 8 healthy donors were incubated for 16 h with 0-50 uM 10058-F4 or DMSO control (x-axis). NK-cell viability was determined using flow cytometry-based cytotoxicity assay, and cell viability was calculated based on untreated cells (0 ng/mL). Error bars represent mean +/ - SEM. (**B**) Diffuse large B-cell lymphoma (DLBCL) lymph node samples from n = 12 patients and multiple myeloma (MM) bone marrow samples from n = 3 patients were incubated with 0-50 uM 10058-F4 (x-axis) for 16 h. Details as in (**A**). (**C**) DLBCL lymph node samples from n = 12 and MM bone marrow samples from n = 3 patients were incubated with rituximab (in the case of DLBCL 0-1000 ng/mL) or daratumumab (in the case of MM, 0-10,000 ng/mL, x-axis) in the presence of PBMCs obtained from healthy donors as effector cells (E:T ratio 40:1) for 16 h. Tumor cell lysis was assessed using a flow cytometry-based cytotoxicity assay. Cell viability was calculated based on untreated cells. Bars and error bars represent mean tumor cell lysis \(\pm\) SEM with mean lysis values of each sample (dots). (**D**) DLBCL samples from n = 12 patients (circles) and MM samples from n = 3 patients (squares) were incubated with 25 uM 10058-F4 and 100 ng/mL rituximab (DLBCL) or daratumumab (MM) in the presence of PBMCs obtained from healthy donors as effector cells (E:T ratio of 40:1) for 16 h. Tumor cell lysis was assessed using a flow cytometry-based cytotoxicity assay. Cell viability was calculated based on untreated cells.