Tumor cell-expressed lipolysis-stimulated lipoprotein receptor negatively regulates T-cell function

Lipolysis-stimulated lipoprotein receptor (LSR) is known as a lipoprotein receptor. LSR is expressed in various solid tumors, including epithelial ovarian, gastric, and colon cancers. High LSR expression is significantly associated with poor prognosis, but its role in cancer has not been fully elucidated. LSR belongs to the Ig protein superfamily, which is conserved in B7 family. Here, we assessed LSR as a novel immune checkpoint molecule. We developed a novel anti-LSR antibody (#27-6 mF-18) that defects antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity activity. The #27-6 mF-18 cross-reacts with both human and mouse LSR. We found that LSR was expressed on 4T1 murine breast cancer cell line. The #27-6 mF-18 exhibited antitumor effects against the 4T1 syngeneic tumor model, a poor immunogenic model refractory to treatment with anti-PD-1 or anti-CTLA-4 antibodies. Compared with control antibody-treated mice, mice treated with #27-6 mF-18 showed significantly increased numbers of CD8+ T cells and a ratio of activated CD8+ T cells infiltrated in the tumor tissue. This antitumor effect was abrogated by CD8+ T-cell depletion through anti-CD8 antibody treatment, indicating that LSR negatively regulates tumor immunity by repressing CD8+ T cells. These findings show that LSR negatively regulates T-cell immune activity. LSR targeting could provide immune checkpoint inhibitors for cancer immunotherapy. Lipolysis-stimulated lipoprotein receptor (LSR), a member of the Ig protein superfamily, is highly expressed in solid tumors. Nonetheless, its role in cancer remains largely uncharacterized. Here, the authors explored the relationship between LSR and tumor growth in an LSR-positive 4T1 syngeneic tumor model, using anti-LSR monoclonal antibodies. Antibody-treated LSR-positive 4T1 mice had increased CD8+ T-cell levels and elevated CD8+ T-cell infiltration in tumor tissue. Anti-LSR antibody treatment significantly inhibited tumor growth, an effect that was abolished upon CD8+ T-cell depletion. The findings suggest that anti-LSR antibodies could be leveraged therapeutically to enhance tumor immunity in LSR-positive tumors.image