Targeting SIRT7 shape an immune-activated microenvironment by both promoting CCL5-induced TILs infiltration and decreasing PD-L1 expression

Background Tumors adapt and survival under immune surveillance by manipulating various adaptive immune-repressive microenvironments. Less than 20% of patients with triple-negative breast cancer benefit from anti-PD-1/PD-L1 therapy, and the absence of tumour-infiltrating lymphocytes (TIL) that primarily comprise macrophage and T cells is likely to be a key factor leading to the immunotherapy failure. These cold tumors are characterised by a reduced immune response and immune cell infiltration in the microenvironment. It has been reported that the anti-PD-L1 therapy is only effective in patients who express PD-L1 and whose tumors are infiltrated by CD8+ T cells. In contrast, the PD-L1+/TIL- type tumors rarely respond to anti-PD-L1 therapy. This study reports that the inhibition of the histone deacetylase SIRT7 not only reduces PD-L1 expression but also enhances M1 macrophage polarization and CD8+T cell infiltration. SIRT7 suppression may facilitate the transition from cold to hot tumors potentially increasing their responsiveness to immunotherapy. Methods SIRT7, PD-L1, and CCL5 protein levels in breast cancer cells and tissues were quantified using western blot (WB) analysis, immunohistochemistry staining (IHC) and multi-immunofluorescence (mIF) assays. Transwell assays were carried out to evaluate cell migration. The mRNA level of SIRT7/CD274/CCL5, IL-10/CD206 (M1 macrophage markers) and iNOS/CD40 (M2 macrophage markers) were determined by q-PCR. Flow cytometry was performed to assess the type and number of immune T cells. CHIP assay was conducted to assess the interaction between the histone deacetylase SIRT7 and the associated DNA promoter of CCL5 regions. respectively. Subcutaneous implantation models were used to assess the in vivo tumor growth. Results Here, we reported that SIRT7 knockdown in immunogenicity mice resulted in restrained growth and activation of infiltrated CD8 ⁺ T cells. SIRT7 inhibition led to CCL5 upregulation and reduced PD-L1 expression. Besides, SIRT7-dependent histone H3K18ac deacetylation inhibited CCL5 transcription, and SIRT7 transcriptionally upregulates PD-L1 expression by directly deacetylating YB-1. Additionally, SIRT7 inhibition promoted CCL5-induced M1-like polarization and CD8+T cell infiltration that were attributed to the mutually reinforced activation. Furthermore, the combined treatment with SIRT7 inhibitor and PD-1 monoclonal antibody significantly restrained tumor growth in mouse model. In clinical breast cancer samples, SIRT7 expression was negatively correlated with CCL5 expression and the number of infiltrating CD8+ T cells. SIRT7 suppression may promote the transition from cold tumors to hot tumors. This suggest that SIRT7 may be a superior target to PD-1/PD-L1 blocking alone. Conclusion SIRT7 inhibition promoted CCL5-induced M1-like polarization and CD8+T cell infiltration. SIRT7 simultaneously enhanced PD-L1 expression, thus weakening T cell-mediated anti-tumor immunity. The cancer progression can be suppressed by SIRT7 inhibition, which leads to decreased PD-L1 protein levels and an elevated immune-activated microenvironment. A combined therapy of SIRT7 inhibitor and anti-PD-1 antibody exerted a synergistic antitumor effect.