Abstract 7289: Activation of toll-like receptors promotes the expression of XBP1s in CLL cells

Abstract Toll-like receptors (TLRs) are a family of transmembrane proteins found in nearly all immune cells and are responsible for recognizing a broad range of pathogenic molecular patterns, including DNA, RNA, sugars, and lipids. Mouse and human B cells express TLRs, contributing to activation of both the innate and adaptive immune responses. Several studies have shown crosstalk between TLR and B cell receptor (BCR) signaling, indicating an important role for TLRs in B cell survival, proliferation, and differentiation. Chronic lymphocytic leukemia (CLL) is the most common B-cell cancer in adults and is known for its variable clinical outcomes. CLL is defined by the accumulation of leukemic cells in the blood, spleens, lymph nodes, and bone marrow. Signals from the lymphoid microenvironment contribute to proliferation of malignant CLL clones, especially in those whose BCR signaling is more pronounced. TLR signaling may amplify BCR-induced cell proliferation and thus accelerate CLL progression. Spliced X-box binding protein 1 (XBP1s) is a transcription factor responsible for endoplasmic reticulum (ER) stress response. XBP1s is vital to plasma cell differentiation and antibody production. Previously, we observed that B cells produce XBP1s in response to treatment with TLR4 ligand lipopolysaccharide (LPS) and TLR9 ligand methylated CpG-DNA (CpG). It is possible that these and other TLR ligands may induce proliferation of specific CLL populations, illuminating the unique role of each TLR in the development of CLL. In this study, we showed that TLR agonists, other than LPS and CpG, were capable of mediating increased expression of XBP1s in mouse splenic B cells. Next, we utilized the Eµ-TCL1 mouse model to investigate the effects of TLR stimulation in CLL cells because CLL developed in these mice resembles the aggressive IGHV-unmutated type of human CLL. When compared to mouse B cells, mouse CLL cells were shown to drastically increase XBP1s expression after TLR stimulation. Consistently, when compared with precancerous B cells isolated from the same mouse, CLL cells expressed higher XBP1s levels in response to TLR ligands. Malignant CLL cells frequently downregulated their expression of stimulator of interferon genes (STING) protein, leading to increased surface expression of the BCR. CLL cells purified from STINGKO/Eµ-TCL1 mice indeed responded to TLR activation by expressing higher levels of XBP1s than those from their control littermates. We thus hypothesize that TLR-induced expression of XBP1s can further modulate BCR signaling in STING-deficient CLL cells to promote malignant progression. Citation Format: Chih-Hang Anthony Tang, Chih-Chi Andrew Hu. Activation of toll-like receptors promotes the expression of XBP1s in CLL cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7289.