Highlights d Synchronous expression of PD-L1 and PD-L2 is dependent on super-enhancers d The PD-L1L2-SE is a super-enhancer located between the genes encoding PD-L1 and PD-L2 d PD-L1L2-SE mediates immune evasion by driving PD-L1 and PD-L2 expression d The activation of PD-L1L2-SE associates with PD-L1 and PD-L2 in cancer patients

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Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma, and up to 30% DLBCL patients eventually died by using first-line chemotherapy regimens.Currently, Bruton tyrosine kinase (BTK) inhibitor (ibrutinib) is one of the most promising medicine in clinical trials for DLBCL, to which about 25% of patients with relapsed or refractory DLBCL are responsive. Thus, it is urgent to discover new druggable targets for DLBCL, especially for patients who are unresponsive to firstline chemotherapy and ibrutinib. Here, we found that MAP 3K7 (TAK1) is required for DLBCL survival. Inhibition of TAK1 by small molecule 5Z7 or genetic silence could massively induce deaths of DLBCL cells. Mechanistically, TAK1 inhibition could dramatically reduce the nuclear factor kappa B (NF-κB) activity. Notably, ibrutinibresistant DLBCL cells also respond to TAK1 inhibition. Database analysis showed that high expression of TAK1 in patients with DLBCL shows poor survival. A subtype of DLBCL patients showed that high expression of both TAK1 and BTK1 is poorly responsive to the current chemotherapy. Moreover, DLBCL cell line with high expression of both TAK1 and BTK1 is resistant to Dox. Simultaneously targeting TAK1 and BTK not only increases cellular toxicity of individual drug but also enhances the sensitivity to Dox. Taken together, we provide convincing evidence to show that kinase TAK1 is a druggable target in DLBCL.Significance of the study: Currently, there is still a significant portion of patients with DLBCL who are unresponsive to first-line chemotherapy. Thus, identification of novel druggable targets such as kinase is critical important. Here, we found that TAK1 inhibition promotes death of DLBCL cells through inhibition of chronic NF-κB signalling. Importantly, TAK1 inhibition overcomes ibrutinib resistance in DLBCL cells.Finally, DLBCL patients with high expression of both TAK1 and BTK showed extremely poor survival. In summary, we provide convincing results to demonstrate a potential important druggable kinase in DLBCL.