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Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
Published on: November 28, 2019
IL-1β Is an Androgen-Responsive Target in Macrophages for Immunotherapy of Prostate Cancer
Deng Wang1,2, Chaping Cheng1, Xinyu Chen1
1State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Shanghai Cancer Institute & Department of Urology, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China.
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.
Insights
Androgen receptor (AR) signaling in prostate cancer (PCa) immune cells promotes tumor growth. Androgen deprivation therapy (ADT) increases IL-1β, creating an immunosuppressive environment. Targeting IL-1β with ADT and anti-PD-1 shows promise for advanced PCa.
Area of Science:
- Immunology
- Oncology
- Endocrinology
Background:
- Androgen receptor (AR) drives prostate cancer (PCa) growth.
- The role of androgens in PCa's immune microenvironment and ADT's impact are poorly understood.
- Immune checkpoint inhibitors are ineffective in advanced PCa due to immunosuppression.
Purpose of the Study:
- Investigate AR signaling in PCa-infiltrated immune cells.
- Determine ADT's effect on the PCa immune microenvironment.
- Identify novel immunotherapeutic targets for advanced PCa.
Main Methods:
- Analysis of AR signaling in tumor-associated macrophages (TAMs) from PCa patients and mice.
- Assessment of IL-1β expression and secretion following ADT.
- Evaluation of IL-1β's role in myeloid-derived suppressor cells (MDSCs) and T cell activation.
- Testing combination therapy of anti-IL-1β, ADT, and anti-PD-1 in a castration model.
Main Results:
- AR signaling is active in PCa TAMs.
- AR represses IL-1β transcription in TAMs.
- ADT removes AR's repression, leading to excessive IL-1β secretion.
- IL-1β induces MDSCs, suppressing cytotoxic T cells and creating an immune-suppressive microenvironment.
- Combination therapy of anti-IL-1β, ADT, and anti-PD-1 demonstrated enhanced anti-cancer effects.
Conclusions:
- IL-1β is a key mediator of immune suppression in advanced PCa under ADT.
- Targeting IL-1β represents a promising immunotherapeutic strategy for advanced PCa.
- Combined anti-IL-1β therapy with ADT and immune checkpoint blockade offers a potent approach for PCa treatment.
