Targeting Nuclear Receptor Coactivator SRC-1 Prevents Colorectal Cancer Immune Escape by Reducing Transcription and Protein Stability of PD-L1

Bcakground: Programmed death-ligand 1 (PD-L1), one of the immunosuppressive molecules, overexpresses in multiple cancers and is critical for their immune escape. We previously showed that the nuclear coactivator SRC-1 promoted colorectal cancer (CRC) progression by enhancing CRC cell viability; however, the role of SRC-1 in CRC immune escape is unclear. Herein, we aim to explore the underlying mechanisms of SRC-1-mediated immune escape in CRC and to find new strategies for treating CRC.Methods: We used CRC cell lines, murine models (subcutaneous grafts and AOM/DSS-induced tumor model), plus CRC patient specimens to delineate the molecular mechanisms by which SRC-1 promotes CRC immune escape. In addition, we used the SRC-1 inhibitor bufalin to further investigate whether targeting SRC-1 could enhance the efficacy of immunotherapy.Findings: We demonstrated that SRC-1 was positively correlated with PD-L1 in human CRC specimens. SRC-1 deficiency significantly inhibited PD-L1 expression in both human and murine CRC cells and retarded murine CRC growth in subcutaneous grafts by enhancing CRC immune escape via increasing tumor infiltration and antitumor activity of effector CD8+ T cells. Genetic ablation of SRC-1 in mice also decreased PD-L1 expression in AOM/DSS-induced murine CRC. These results suggest that tumor-derived SRC-1 promotes CRC immune escape by enhancing PD-L1 expression. Mechanistically, SRC-1 activated JAK-STAT signaling by inhibiting SOCS1 expression and coactivated STAT3 and IRF1 to enhance PD-L1 transcription as well as stabilized PD-L1 protein by inhibiting proteasome-dependent degradation mediated by speckle type POZ protein (SPOP). Pharmacological inhibition of SRC-1 improved the antitumor effect of PD-L1 antibody in both subcutaneous graft and AOM/DSS-induced murine CRC models.Interpretation: We identified a crucial role of SRC-1 in facilitating CRC immune escape and targeting SRC-1 in combination with PD-L1 antibody immunotherapy may be an attractive strategy for CRC treatment.Funding: This study was supported by the National Natural Science Foundation of China and Natural Science Foundation of Ningbo.Declaration of Interest: The authors have declared that no conflict of interest exists.Ethical Approval: All animal experiments were conducted under protocols approved by the Laboratory Animal Center of Xiamen University. For experiments using human specimens, all specimens were anonymously coded in accordance with the Declaration of Helsinki. The study protocol that conformed to the ethical guidelines was approved by the Medical Ethics Committee at school of medicine, Xiamen University.