Tumour microenvironment in Diffuse Large B Cell Lymphoma and link to response: standard-of-care and immunotherapies

Aim/goals:

1. Understand mechanisms of drug resistance in a subset of DLBCL.
2. Investigate temporal and spatial heterogeneity of tumours to identify immune targets

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma and is curable in 60% of patients with chemo-immunotherapy. Relapsed DLBCL (rDLBCL) is usually resistant to further chemotherapy but 40% respond to cellular (immune) therapy, such as CAR-T therapy.  Our group’s research focuses on understanding the biology of DLBCL, from the perspective of the tumor and the immune system, to maximize the potential of cure in these high-risk patients. 

Aim 1. Mechanisms of drug resistance: We used BH3 profiling to understand why tumor cells don’t die following chemotherapy.  We published that a third of DLBCLs are incapable of undergoing mitochondrial apoptosis and this functional defect is associated with resistance to chemotherapy but not mutations in the pro-apoptotic proteins within the mitochondrial pathway, such as BAX, BAK, BIM. Thus, other unknown genomic and transcriptomic drivers must underlie these functional defects.

Aim 2. Prospective treatment assignment based on molecular/spacial characterization.  We show that specific mutations in DLBCL may change the immune tumor micro-environment.  For example, DLBCL with STAT6 mutations secrete cytokines that recruit T cells to support their growth.  We will use CODEX highly multiplexed imaging technology to study the immune micro-environment (40+ immune markers) in tissue micro-arrays containing over 200 DLBCL cases. Full genomes and transcriptomic profiling of certain cases can provide additional insights into how other mutations can potentially shape their immune support.

Overall, sequencing proved from MOHCCN will synergize with our funded projects to identify new therapeutic vulnerabilities and potentially cure more patients with high-risk DLBCL.