Project Term
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Project Summary
Richter’s transformation (RT) refers to the development of an aggressive lymphoma in patients with a prior diagnosis of chronic lymphocytic leukemia (CLL) that remains uncured, even with the current T-cell based immunotherapy such as chimeric antigen receptor (CARs) T cells. Fibroblastic reticular cells (FRCs) modulate T cells in secondary lymphoid organs (SLOs) via toll-like receptors (TLR) and promote the expression of PD-L1 and PD-L2 to modulate and suppress T cells especially cytotoxic T cells, however, the role of FRCs is not well defined in CLL or RT. Here, we propose to perform mechanistic and translational studies to understand if and how TLR9 plays a critical role in FRC-modulated suppressive T cell activities, and to determine whether targeting TLR9 in FRCs can reactivate T cell immunity and improve treatment outcome in RT.
Lay Abstract
The project is the first to study stromal cells within different secondary lymphoid organs for their contribution to Richter’s transformation in CLL. This study is innovative and relevant to blood cancer in multiple ways. [1] The project is built on previously published and our recent findings of CLL and DLBCL exposed FRCs that suppress T cell immunity. [2] Targeting FRCs and suppressing the immunomodulating functions of FRCs and enhances anti-PD-1 immunotherapy. [3] CLL and DLBCL cells induce the stretching, pulling and gap formation of fibroblasts, the phenotypes typically seen in cancer-associated fibroblasts (CAFs). Overall, this work will demonstrate the relevance of fibroblasts for CLL or other B cell lymphoproliferative disorder that has not been studied extensively and provide new therapeutic strategies to improve RT therapy.
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