This week we profile a recent publication in Cancer Discovery from the laboratory of Dr. Christian Steidl (pictured) at BC Cancer.
Can you provide a brief overview of your lab’s current research focus?
My lab is focused on the pathogenesis of lymphoid cancers and translational research with the goal to develop targeted treatments and novel biomarker assays. Seminal findings from our research group have produced a large foundation of published data describing B-cell lymphoma-associated genomic and phenotypic features associated with treatment failure to standard of care using discovery genomics. Recently, we significantly contributed to a more detailed understanding of the tumour microenvironment, and the pathogenic and clinical importance of cellular crosstalk within an ecosystem of malignant and non-malignant immune cells. Through our genomics-based discovery platforms, we shaped the concept of acquired immune privilege in lymphoid cancers, postulating that somatically acquired gene mutations increase cellular fitness through reduced immunogenicity, including loss of HLA class I and II expression, surface molecule expression blunting immune attack, and induction of regulatory tumour microenvironments.
What is the significance of the findings in this publication?
In our most current integrative genomics studies of RNAseq and high-resolution copy number analysis in 347 diffuse large B cell lymphoma (DLBCL) patients uniformly treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) from a BC Cancer population registry-based cohort (Ennishi et al, Cancer Discovery 2019), we discovered the genetic and molecular features associated with MHC class I and II loss. We uncovered that MHC class II loss is most relevant in germinal center B (GCB) cell-type DLBCL as loss is associated with poor treatment outcome, a specific set of gene mutations characteristic of GCB-DLBCL, and an expression program that is associated with an immunologically “cold” microenvironment with a reduced T cell infiltrate. Most strikingly, somatic EZH2 hotspot mutations were most associated with MHC class II loss, and mouse modelling confirmed a causal link between EZH2 mutation and epigenetic silencing of the MHC locus. Excitingly, MHC expression can be restored by EZH2 inhibitor treatment increasing the immunogenicity of tumour cells. Thus, our data strongly supports a preclinical rationale of combination therapy with epigenetic reprogramming (e.g. EZH2 inhibitors) and immunotherapies (e.g. PD1 inhibitors) that rely on antigen presentation capacity.
What are the next steps for this research?
The next steps are to test combination approaches (e.g. EZH2 inhibitors, PD1 inhibitors) in clinical trials focusing on well-defined patient subsets. In the context of these trials, mutation status of epigenetic modifiers (eg. EZH2, CREBBP mutations) and MHC expression status need to be tested for their power to predict patients’ outcomes. Moreover, we need to study HLA-dependent and -independent antigen presentation/expression to tailor novel immunotherapeutic approaches to individual patients. The composition, functional state, and spatial architecture of the tumour microenvironment will likely be a critical biological marker for treatment response to these novel therapies. The most exciting, novel immunotherapeutic approaches include checkpoint inhibitors, antibody therapies (incl. drug conjugates, bi-specific antibodies), T cell receptor mimic antibodies, tumour-associated antigen-specific cytotoxic T cells and CART cells.
This work was funded by:
– BC Cancer Foundation
– Terry Fox Research Institute
– Canadian Cancer Society Research Institute
– Genome Canada, Genome BC
– Canadian Institutes of Health Research
– Michael Smith Foundation for Health Research
– Paul G. Allen Frontiers Group
