IL‐1β Is an Androgen‐Responsive Target in Macrophages for Immunotherapy of Prostate Cancer

Abstract

Great attention is paid to the role of androgen receptor (AR) as a central transcriptional factor in driving the growth of prostate cancer (PCa) epithelial cells. However, the understanding of the role of androgen in PCa-infiltrated immune cells and the impact of androgen deprivation therapy (ADT), the first-line treatment for advanced PCa, on the PCa immune microenvironment remains limited. On the other hand, immune checkpoint blockade has revolutionized the treatment of certain cancer types, but fails to achieve any benefit in advanced PCa, due to an immune suppressive environment. In this study, it is reported that AR signaling pathway is evidently activated in tumor-associated macrophages (TAMs) of PCa both in mice and humans. AR acts as a transcriptional repressor for IL1B in TAMs. ADT releases the restraint of AR on IL1B and therefore leads to an excessive expression and secretion of IL-1𝜷 in TAMs. IL-1𝜷 induces myeloid-derived suppressor cells (MDSCs) accumulation that inhibits the activation of cytotoxic T cells, leading to the immune suppressive microenvironment. Critically, anti-IL-1𝜷 antibody coupled with ADT and the immune checkpoint inhibitor anti-PD-1 antibody exerts a stronger anticancer effect on PCa following castration. Together, IL-1𝜷 is an important androgen-responsive immunotherapeutic target for advanced PCa.

Androgen deprivation triggers a cytokine signaling switch to induce immune suppression and prostate cancer recurrence

“…The specific signal may vary depending on the TME context. For example, there is no evidence of TNF switching in the Hi-MYC GEMM, or in human prostate cancers while in some PTEN-deficient GEMMs, IL1ß triggers myeloid immune suppression (68). However, we propose that the cellular interactions within the TME are likely to be similar in human nmCRPC and mCRPC as well as GEMMs.…”

Expanding horizons in overcoming therapeutic resistance in castration-resistant prostate cancer: targeting the androgen receptor-regulated tumor immune microenvironment

“…In CRPC, AR signaling remains active despite androgen depletion through ADT. Ligand-independent activation is a mechanism contributing to AR activation in CRPC, wherein alternative signaling pathways bypass the need for androgens 4 – 6 . Growth factor receptors (e.g., EGFR and IGF-1R) and intracellular signaling cascades (e.g., PI3K/Akt and MAPK) activate AR signaling without androgens.…”

“…Furthermore, ADT has been associated with overcoming the inhibitory effects of AR on IL-1β, thus leading to excessive expression and secretion of IL-1β in TAMs. IL-1β induces MDSC accumulation, thereby inhibiting the activation of cytotoxic T cells and leading to an immune suppressive microenvironment ( Figure 2 ) 4 . Moreover, androgen signaling suppresses T-cell immunity against cancer in males by upregulating the expression of USP18, and consequently inhibiting TAK1 phosphorylation and subsequent activation of NF-κB in antitumor T cells.…”

“…Recent studies have highlighted the effects of AR signaling on immune cell function and immune-mediated anti-tumor responses within the tumor microenvironment 2 , 3 . Androgens modulate the expression of immune checkpoint molecules, cytokines, and chemokines, thereby shaping the immune landscape of tumors 4 , 5 . Targeting the TIME component regulated by the AR is a promising strategy to overcome therapeutic resistance in CRPC.…”

Silencing SPP1 in M2 macrophages inhibits the progression of castration-resistant prostate cancer via the MMP9/TGFβ1 axis

“…Nevertheless, recent research has revealed a high abundance of macrophages in CRPC tissues ( 3 ). In addition, a high abundance of macrophages can suppress T cell activity, leading to an immunosuppressive microenvironment that promotes castration-resistant progression of PCa ( 9 ). Thus, targeting macrophages has emerged as a potential approach for PCa treatment ( 10 ).…”