BCG HSP70 Reprograms Macrophages via Central Trained Immunity to Suppress Prostate Cancer

Area of Science:

• Immunology
• Cancer Biology
• Metabolic Reprogramming

Background:

• Trained immunity holds promise for cancer immunotherapy but faces challenges with current inducers like BCG due to safety concerns and undefined components.
• BCG-derived heat shock protein 70 (BCG HSP70), known as Dnak, was previously considered only an immune adjuvant, with its role in trained immunity unexplored.

Purpose of the Study:

• To identify Dnak as a safe and defined inducer of trained immunity.
• To investigate Dnak's mechanism in establishing trained immunity and its efficacy in preclinical cancer models.
• To explore the potential of combining Dnak-induced trained immunity with cancer vaccines.

Main Methods:

• Dnak was tested as a trained immunity inducer in mouse models, assessing epigenetic and metabolic reprogramming of hematopoietic stem cells.
• Prostate cancer models were used to evaluate Dnak's effect on tumor growth, with studies involving bone marrow transplantation.
• Macrophage function, including glycolysis and M1 polarization, was analyzed, alongside the role of O-GlcNAcylation.
• Combination therapy with Dnak and a tumor vaccine was assessed for tumor control and immune memory generation.

Main Results:

• Dnak was identified as a safe inducer of durable central trained immunity, protecting against bacterial infection via stem cell reprogramming.
• A single Dnak pre-treatment significantly inhibited prostate tumor growth, transferable via bone marrow transplantation and dependent on tumor-associated macrophages.
• Dnak-trained macrophages showed enhanced glycolysis, mTOR/HIF-1α activation, and M1 polarization, with O-GlcNAcylation identified as a key regulator.
• Combination therapy resulted in superior tumor control, favorable tumor microenvironment modulation, and durable memory T cell responses.

Conclusions:

• BCG HSP70 (Dnak) is a safe, defined, protein-based inducer of trained immunity with significant preclinical efficacy in cancer immunotherapy.
• Dnak reprograms hematopoietic stem cells, leading to enhanced macrophage function and tumor inhibition, offering a novel therapeutic strategy.
• Combining Dnak-induced trained immunity with cancer vaccines demonstrates translational potential for improved cancer treatment outcomes.