Cutaneous T cell lymphomas (CTCLs) are incurable non-Hodgkin lymphomas of the skin-homing T cell. Median survival for patients with advanced CTCL is less than 5 years, but survival can vary widely from 3 months to 15 years. Without the molecular basis for this heterogeneity, all stage-matched patients are treated similarly. We found that the vast majority of CTCLs display signs of T cell exhaustion, a dysfunctional phenotype associated with chronic T cell receptor (TCR) activation. PD1-mutant CTCLs were the exceptions. PD1 is a coinhibitory receptor that mediates T cell exhaustion in vivo. PD1-mutant CTCLs had low levels of exhaustion markers, proliferated robustly, and had a significantly worse prognosis. Median survival for patients with PD1-mutant CTCLs is 1 year (compared to 7 years for PD1-wild-type CTCLs). Based on our own preliminary RNA-Seq data, we hypothesize that PD1-mutant CTCLs harbor profound differences in TCRdependent signaling, metabolism, and transcription. In this proposal, we aim to establish these PD1-dependent differences in primary patient samples using high-dimensional assays. In parallel, we will use a combination of small molecule inhibitors and CRISPR to mechanistically dissect the molecular basis for these differences in primary CTCLs in vitro and in patient derived xenografts in vivo. Collectively, these experiments will form the basis for novel rationally designed therapeutic strategies that target the most aggressive CTCL subtypes.
|Effective start/end date||7/1/21 → 6/30/26|
- Leukemia & Lymphoma Society (1377-21)
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