Pltp Regulates BCR Signaling and Tumor Microenvironment in Diffuse Large B-Cell Lymphoma through Reprogramming of Lipid Metabolism Environment

Diffuse large B-cell lymphoma (DLBCL) is the most common type among all non-Hodgkin's lymphoma (NHL). Approximately 60% of the patients can be cured using the standard R-CHOP regimen of chemotherapy, but around 40% still die due to relapse or refractory disease. Therefore, it is necessary to explore the new molecular mechanisms of DLBCL to find targets for more precise treatment. Reprogramming of lipid metabolism is closely related to a variety of tumor processes, including diffuse large B-cell lymphoma (DLBCL). However, phospholipid transfer protein (PLTP), which is highly relevant to lipid metabolism, has not been reported in lymphoma. Our group previously found that PLTP was highly expressed in DLBCL and was associated with poor prognosis and increased infiltration of M2 macrophages; knockdown of PLTP inhibited tumor cell line survival and alleviated tumor progression in mice, and the concomitant reduction in membrane cholesterol and BCR signaling may be associated with reduced cholesterol transport by ATP-binding cassette transporter A1 (ABCA1). Simultaneous knockdown followed by co-culture with monocytes revealed reduced polarization and activation of M2-type macrophages. In our study, we hypothesize that high PLTP expression in DLBCL causes cholesterol accumulation to enhance lipid raft which will activate BCR signaling. On the one hand, PLTP promotes the malignant phenotype of lymphoma cells; on the other hand, it induces tumor-associated macrophage polarization to reshape the microenvironment, leading to immune escape. This project aims to find out the specific mechanisms of how PLTP regulates DLBCL self-proliferation and reshapes the tumor-microenvironment through cholesterol metabolism at the tissue, cellular, and animal levels. The results will provide a new target for the precise treatment of DLBCL from a new perspective of lipid metabolism.

No relevant conflicts of interest to declare.