BET Inhibition Sensitizes Immunologically Cold Rb-Deficient Prostate Cancer to Immune Checkpoint Blockade

Area of Science:

• Oncology
• Immunology
• Cancer Genomics

Background:

• Non-T-cell-inflamed "cold" tumor microenvironments (TME) limit immune checkpoint blockade (ICB) efficacy.
• Loss-of-function (LOF) in the retinoblastoma (Rb) tumor suppressor is common in cancer, linked to poor prognosis and treatment outcomes.
• Rb LOF influences tumor cell plasticity and the TME, impacting therapeutic responses.

Purpose of the Study:

• To investigate how Rb LOF affects the TME and ICB responsiveness.
• To evaluate therapeutic strategies targeting molecular consequences of Rb loss to enhance ICB efficacy.
• To explore the role of bromodomain and extraterminal (BET) domain inhibition (BETi) in reprogramming the TME.

Main Methods:

• Bioinformatics analysis of human tumors to assess Rb LOF impact on immune TME.
• Isogenic murine models of Rb-deficient prostate cancer for in vitro and in vivo studies.
• Evaluation of BETi (JQ1), ICB, and androgen deprivation therapy efficacy in combination and alone.

Main Results:

• Rb LOF was associated with non-T-cell-inflamed tumors and reduced immune infiltration.
• BETi JQ1 increased immune cell infiltration by activating tumor cell STING/NF-κB and type I IFN signaling.
• BETi sensitized Rb-deficient prostate cancer to ICB, mediated by macrophages and T-cells.

Conclusions:

• BET inhibition can reprogram the "cold" TME in Rb-deficient tumors.
• Activation of STING/NF-κB/IFN signaling by BETi enhances ICB efficacy in Rb-deficient prostate cancer.
• Combination therapy of BETi and ICB warrants clinical investigation for Rb-deficient prostate cancer.