## 3 Discussion
MYC may be additionally involved in other processes relevant to immune-mediated tumor cytotoxicity, including inhibiting ferrotposis and necroptosis [36; 37], contributing to evasion from anti-tumor immune responses via non-apoptotic mechanisms of programmed cell death. The lymphoma-intrinsic MYC-mediated suppression of T-cell activation may occur via the increased secretion of immunosuppressive cytokines, inhibition of inflammatory signaling [38] or modulation of accessory molecules involved in immune synapses and the immunosuppressive tumor microenvironment. Investigating these immunosuppressive mechanisms associated with MYC is relevant for future studies. A major challenge in this context is the absence of proper in vivo models, as continuous overexpression or complete inhibition of MYC can be lethal for the host [39]. A tetracycline-regulated model of MYC-induced T-cell acute lymphoblastic leukemia has been developed [40]. However, in vivo models are often immunocompromised, which complicates the study of immunotherapeutic approaches. Novel in vivo models incorporating the human immune system and engrafted with patient-derived tumor xenografts [41] probably face challenges with high toxicity induced by direct MYC inhibitors. MYC-mediated escape from currently used immunotherapeutic approaches has important clinical implications. First, it may explain why MYC overexpressing lymphomas are often refractory to R-CHOP immunochemotherapy. Second, it suggests that the treatment of MYC-driven malignancies could be improved by additional modulation of the MYC-mediated immune escape mechanisms. The challenge for the clinic is determining the optimal way to inhibit MYC. Despite widely available preclinical approaches to inhibit MYC [19; 24], the early clinical use of direct MYC inhibitors did not proceed into clinical practice due to complicated drug development and undesired side effects [42]. MYC also exerts numerous physiological functions in NK-cells and T-cells [43; 44; 45]. Moreover, in our experimental approach, we have observed toxic effects of 10058-F4 on immune effector cells at concentrations exceeding 50 \(\upmu\)M.  
To translate our findings into clinical applicability, we propose to interfere with the mechanisms by which MYC overexpressing tumors escape from immunotherapeutic approaches. For instance, since MYC overexpressing lymphomas escape rituximab-mediated cytotoxicity by downregulating CD20, patients may benefit from agents that upregulate CD20, such as the histone deacetylase (HDAC) inhibitor valproate [46], the chemotherapeutic gemcitabine [47] or PIM kinase inhibitors [21]. Valproate and gemcitabine are clinically available and show beneficial results in DLBCL patients [48; 49]. Alternatively, agents that downregulate anti-apoptotic proteins BCL-2, MCL-1, XIAP and/or survivin may be considered. For instance, venetoclax is an oral BCL-2 inhibitor that was considered a promising addition to R-CHOP, especially in lymphoma patients with MYC and BCL-2 overexpression [50]. However, the addition of venetoclax to the more intensive immunochemotherapeutic regimen EPOCH-R resulted in considerable toxicities [51]. Nevertheless, the fact that in our study the expression of anti-apoptotic BCL-2 was not restored in repaired subclones suggests that enhanced ADCC after MYC modulation is not solely influenced by BCL-2, highlighting the multifaceted mechanisms of MYC to escape from anti-tumor immune responses. Therefore, other agents that inhibit several anti-apoptotic proteins simultaneously may be more beneficial. The experimental drug FL118 downregulates MYC and the anti-apoptotic proteins survivin, MCL1 and XIAP [52; 53], can modulate immune escape induced by the bone marrow microenvironment [28] and has shown promising pre-clinical activity in MM [27]. Of course, for each of these agents, careful studies are needed to determine an optimal dosage that has little or no toxic effects on NK-cells and T-cells. In addition, agents that improve the activity of NK-cells and T-cells could be advantageous.