W160 - Identifying Therapeutic Vulnerabilities of B Cell Tumors Disseminating into Immune Privileged Sites

Abstract Text: Diffuse large B-cell lymphomas (DLBCLs) that infiltrate non-lymphoid tissues, including immune-privileged sites such as the brain, represent a critical clinical challenge, due to a lack of mechanistic understanding.

BTG1 genetic alterations are found in up to 70% of DLBCLs with high frequency of non-lymphoid tissue infiltration and poor prognosis. We find that they are the top mutations in circulating tumor DNA from the cerebrospinal fluid of DLBCL patients with brain infiltration. Taking advantage of our unique Btg1Q36H mutant conditional mouse model, in which Btg1Q36H B cells outcompete wild-type cells through a faster response to T cell signals and facilitated Myc protein synthesis, and rapidly transform into disseminated B cell lymphomas; we set out to identify signals driving Btg1Q36H B cells’ competitive fitness.

We found that interleukin-21 (IL-21)-induced signaling is the top upregulated pathway in Myc-positive Btg1Q36H cells and is enriched in BTG1 mutant DLBCLs. This is associated with elevated levels of IL-21 receptor (IL-21R) and a lower IL-21 threshold for downstream STAT3 activation. Btg1Q36H B cells show an IL-21- and T cell help-dose-dependent competitive advantage. Knocking down IL-21R rescues their advantage.

These findings identify the IL-21-STAT3 axis as a critical driver of Btg1Q36H B cells’ competitive fitness and potential vulnerability of derived disseminated DLBCLs. We further generated a mouse pre-clinical model of brain-infiltrating DLBCL, to test the efficacy of targeting this axis to kill brain-infiltrating tumor cells. Future translation is envisioned using IL-21-blocking antibodies and STAT3 inhibitors currently in clinical trials for other diseases.