Unlocking the dual role of LSD1 in tumor immunity: innate and adaptive pathways

Abstract

The roles of innate and adaptive immunity are crucial in both the development of cancer and its response to treatment. Numerous studies have demonstrated that histone lysine-specific demethylase 1 (LSD1) is overexpressed in various cancers. Elevated levels of LSD1 intricately modulate immune checkpoints, the function of immune cells, and the expression of immunomodulators, impacting both innate and adaptive immunity. Moreover, compelling evidence suggests that inhibiting LSD1 enhances tumor immunity, suppresses tumor growth, and improves the effectiveness of immunotherapy. However, a comprehensive classification of LSD1's role in both innate and adaptive immunity is lacking. In this review, we outline the role of LSD1 in tumor immunity in terms of both innate and adaptive immunity, summarizing the mechanisms associated with LSD1-mediated tumor immunity and its potential regulatory capacity in tumor immune escape. Finally, we summarize the research status of LSD1 inhibitors in tumor immunotherapy, which be valuable for promoting the development of effective LSD1-targeted agents used as combination immunotherapy drugs.

Keywords: Cancer immunotherapy; Immune cell; Immune checkpoint blockade; LSD1; Tumor microenvironment.

Figure 1

LSD1's regulation on innate immunity. A. LSD1 regulates the anti-tumor activity of NK cells through two pathways: LSD1 inhibition up-regulated the expression of NK cell ligand on AML; Scaffolding inhibitors reduce oxidative phosphorylation and glycolysis of NK cells and induce mitochondrial depletion of reactive oxygen species and antioxidant glutathione. B. LSD1 inhibition promotes the differentiation of TAM into M1 macrophages, promotes the infiltration of M1 macrophages, and inhibits the progression of TBNC. C. LSD1 inhibition decreased the proportion of CAFs in TME and inhibited the progression of TNBC. Inhibition of LSD1 can restore the expression of IRF8 in MDS progenitor cells, promote CD141^Hi cDCs differentiation.

Figure 2

LSD1 regulates antigen presentation and T cell activation. Inhibition of LSD1 leads to upregulation of MHC-I expression in different cell types, promoting T cell activation and infiltration. In melanoma, loss of LSD1 results in upregulation of MHC-I gene expression. LSD1 deficiency leads to accumulation of dsRNA by reducing RISC components, which activate the IFN pathway subsequently, and then upregulate MHC-I expression. In SCLC, inhibition of LSD1 promotes enhanced tumor immunogenicity and increased CD8+ T cell activation and infiltration, which is achieved by restoring MHC-I expression, triggering intrinsic IFN signaling, and other pathways. In MSCs, LSD1 inhibition also promotes MHC-I expression by inducing dsRNA stress, while upregulating the level of ISGs, IFN, and PRRs. Additionally, Inhibition of LSD1 up-regulates the expression of MHC-II in macrophages and promotes antigen presentation to CD4+T cells.

Figure 3

LSD1 interferes with the anti-tumor immune process by regulating the expression of TGF-β, VEGF and Chemokines. TGF-β: In GC and NSCLC, LSD1 positively regulates TGF-β and promotes cancer cell metastasis, while in melanoma and CRC, LSD1 negatively regulates TGF-β, while eliminating LSD1 and TGF-β and jointly blocking PD-1 can significantly enhance CD8+ T cell infiltration and cytotoxicity. VEGF: Stabilized by LSD1, HIF1α collaborates with CBP and MTA1 to boost VEGF-triggered angiogenesis in human breast cancer. Chemokines: In TNBC and SCCOHT, inhibition of LSD1 can enhance the secretion of chemokines such as CCL5, CXCL9, CXCL10 and CCL2, and recruit CD8+ T cells into the TME to play a powerful killing ability.

Figure 4

LSD1 plays a crucial role in tumor immunotherapy. A. In TNBC, inhibition of LSD1 resulted in increased expression of CCL5, CXCL9, CXCL10, and PD-L1, which attracted CD8+ T-cells into the TME and acted as killers. The combination of HCI-2509 and PD-1 antibodies further enhanced the therapeutic effect. B. Inhibition of LSD1 results in decreased expression of PD-L1 and CD47 on the surface of CC tumor cells. The therapeutic effect of LSD1 inhibitors is enhanced when used in conjunction with PD-L1 or CD47 antibodies. Lack of LSD1 results in decreased expression of PD-L1 in GC exosomes, increased T cell activity, and restoration of T cell ability to attack tumors. C. Inhibition of LSD1 in tumor cells enhanced CAR T cell cytotoxicity against neuroblastoma, whereas LSD1 inhibition in CD19-CAR T cells also promoted their proliferation rate and cytokine secretion.