Sphingosine kinase 1 counteracts chemosensitivity and immune evasion in diffuse large B cell lymphoma cells via the PI3K/AKT/PD-L1 axis

• Published in: International immunopharmacology 2024-12, Vol.143 (Pt 2), p.113361, Article 113361
• Main Authors: Liu, Dan, Liu, Longlong, Li, Haiming, Huang, Zhenqian, Wang, Yaya
• Format: Article
• Language: English
• Subjects: Animals; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Chemoresistance; Diffuse large B-cell lymphoma; Doxorubicin - pharmacology; Drug Resistance, Neoplasm; Humans; Immune escape; Immune Evasion; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - immunology; Lymphoma, Large B-Cell, Diffuse - metabolism; Mice; Mice, Inbred BALB C; Phosphatidylinositol 3-Kinases - metabolism; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; SphK1; T cells; Tumor Escape - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.113361

•SphK1 loss suppresses DLBLC cell proliferation and resistance to doxorubicin.•Targeting SphK1 affects DLBCL cell resistance to T cell cytotoxicity.•Inhibition of SphK1 changed the activity of CD8 + T cells.•Knockdown of SphK1 inhibits the activation of the PI3K/AKT/PD-L1 signaling.•Targeting SphK1 enhances doxorubicin-mediated tumor inhibition, T cell immune evasion. Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive neoplasm of lymphatic system that represent 38–58 % of non-Hodgkin lymphoma. Chemoresistance and immune escape constitute the major obstacles to the treatment of patients. Sphingosine kinase 1 (SphK1) is involved in multiple processes of cancer. Up to now, little research focuses on its function in DLBCL. In the current research, GEPIA and human Protein Atlas databases confirmed high expression of SphK1 in DLBCL tissues. Analogously, increased expression of SphK1 were determined in DLBCL tissues and cells. Intriguingly, knockdown of SphK1 suppressed DLBCL cell viability and increased chemosensitivity to doxorubicin by decreasing cell viability and increasing caspase-3 activity. Reversely, SphK1 elevation facilitated cancer cell resistance to doxorubicin. Furthermore, loss of SphK1 increased the productions of inflammatory cytokine IFN-γ and TNF-α, but reduced IL-10 levels in co-culture model of CD8 + T cells and DLBCL cells. Importantly, SphK1 knockdown enhanced T cell cytotoxicity to DLBCL cells, while its elevation restrained the ability of T cells to kill cancer cells. Concomitantly, targeting SphK1 enhanced the percentage of CD8 + T cells and attenuated co-culture-evoked CD8 + T cell apoptosis, indicating the important roles in T cell escape. Mechanically, SphK1 overexpression enhanced and its knockdown suppressed activation of the PI3K/AKT/PD-L1 pathway. After blockage of this pathway by its antagonist, the beneficial effects of SpHK1 on chemoresistance and immune escape were abrogated. In vivo, targeting SphK1 inhibited tumor growth and enhanced the anti-tumor efficacy of doxorubicin in DLBCL xenograft tumor, concomitant with the inhibition of the PI3K/AKT/PD-L1 signaling. Collectively, SphK1 knockdown counteracted chemoresistance and immune escape from T cell killing by inhibiting the PI3K/AKT/PD-L1 pathway. Therefore, targeting SphK1 may represent a promising therapeutic strategy for overcoming chemoresistance and immune escape in DLBCL.