The Ap-2α/Elk-1 axis regulates Sirpα-dependent tumor phagocytosis by tumor-associated macrophages in colorectal cancer

Abstract

The inhibitory receptor signal regulatory protein-α (Sirpα) is a myeloid-specific immune checkpoint that engages the "don't eat me" signal CD47, which is expressed on tumor and normal tissue cells. However, the profile and regulatory mechanism of Sirpα expression in tumor-associated macrophages (TAMs) are still not clear. Here, we found that the expression of Sirpα in TAMs increased dynamically with colorectal cancer (CRC) progression. Mechanistically, CRC cell-derived lactate induced the nuclear translocation of the transcription factor Ap-2α from the cytoplasm in TAMs. Ap-2α functioned as a transcription factor for Elk-1 by binding to the conserved element GCCTGC located at −1396/−1391 in the mouse Elk-1 promoter. Subsequently, the Elk-1 protein bound to two conserved sites, CTTCCTACA (located at −229/−221) and CTTCCTCTC (located at −190/−182), in the mouse Sirpα promoter and promoted Sirpα expression in TAMs. Functionally, the macrophage-specific knockout of Ap-2α notably promoted the phagocytic activity of TAMs and suppressed CRC progression, whereas these effects were prevented by the transgenic macrophage-specific expression of Elk-1, which regulated TAM phagocytosis and CRC development in a Sirpα-dependent manner. Furthermore, we showed that Elk-1 expression was positively correlated with Sirpα expression in TAMs and was associated with poor survival in CRC patients. Taken together, our findings revealed a novel mechanism through which CRC evades innate immune surveillance and provided potential targets for macrophage-based immunotherapy for CRC patients.Signal Transduction and Targeted Therapy (2020) 5:35; https://doi.

Tumor-Associated Macrophages (TAMs) in Colorectal Cancer (CRC): From Mechanism to Therapy and Prognosis

“…With our improved understanding of TAM function and mechanisms in CRC, more promising therapies based on different principles are on the way. Recent studies have shown that TAMs can express PD-1, PD-L1, and myeloid-derived specific immune checkpoint signal regulatory protein-α (SIRPα) in the TME of CRC [171]. Therefore, immunotherapy targeting TAMs may synergistically enhance the efficacy of immunotherapy with immune checkpoint inhibitors such as anti-PD-1, PD-L1, and CTLA-4 antibodies, thereby enabling more CRC patients to benefit from immunotherapy.…”

In-depth Proteomic Profiling Captures Subtype-specific Features of Craniopharyngiomas

“…The BRAF V600E mutation in PCP may phosphorylate MAPKs to activate ELK1 and ESSRA 48,49 . Interestingly, ELK1 plays a role in the regulation of immune cells in tumor microenvironments 50,51 . Moreover, ERR1 is associated with the regulation of the balance between tumor cytolytic lymphocytes and immunosuppressive M2 macrophages in melanomas 52 .…”

Nanoparticles Targeting Innate Immune Cells in Tumor Microenvironment

“…Many recent studies have demonstrated that the inhibition of the CD47-signal regulatory protein-α (Sirpα) signaling is a promising target for activating macrophage phagocytosis. Representing a “don’t eat me” signal, CD47 is overexpressed on the surface of cancer cells in many tumor types [ 54 ]. When Sirpα from macrophages binds to CD47, it controls and blocks the activation of macrophage phagocytosis [ 55 ].…”