ICML 2023 | Epigenetic regulation of immune microenvironment interactions in lymphoma

So epigenetics are pretty central to the development of germinal center B cells at various different cell state transitions either entering the germinal center or transitioning from centroblast to centrocytes. During this normal transition, there are quite a large shift in the epigenetic programs that control normal programs of T-cell interaction, such as in centroblast, these are all downregulated as the cells are undergoing somatic hypermutation. And then as you transition into centrocytes, they are upregulated again to mediate interaction with T follicular helper cells and positive selection in response to CD40. So these are normally regulated during B-cell development. And what happens in B-cell lymphomas is that they acquire, particularly in follicular lymphoma, they acquire mutations and chromatin modifying genes like CREBBP and EZH2 and KMT2D, and these alter the normal epigenetic programming of these enhancers that are dynamically regulated during normal B-cell development. So what we and others have found, this works been led primarily by Ari Melnick’s group and Laura Pasqualucci’s group, our own group and some others. And what we found is that the mutations in these chromatin modifying genes, deregulate these normal processes of epigenetic shifts during B-cell development. And primarily we found, particularly with respect to EZH2 and CREBBP mutations, that it results in a downregulation of antigen presentation and immune synapse genes that mediate interaction with T follicular helper cells and other cells within the microenvironment. So these are potentially targetable through interventions like EZH2 inhibitors or particularly selective HDAC inhibitors and could restore these programs independently of mutation status in B-cell lymphoma.