Rapamycin Prevents Surgery-Induced Immune Dysfunction in Patients with Bladder Cancer

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Mechanistic target of rapamycin (mTOR) regulates tumor growth and T-cell responses, complicating cancer treatment with mTOR inhibitors.
• Preclinical studies suggest rapamycin has biphasic effects: high doses inhibit tumor growth, while low doses enhance T-cell immunity.
• Surgery can induce T-cell exhaustion, promoting cancer metastasis and reducing immunotherapy effectiveness.

Purpose of the Study:

• To investigate the effects of low-dose rapamycin on tumor and T cells in bladder cancer patients undergoing cystectomy.
• To explore the mechanistic insights using MB49 syngeneic murine bladder cancer models.
• To assess the translational relevance of rapamycin's biphasic effects in a clinical setting.

Main Methods:

• Monitored mTOR complex 1 (mTORC1) inhibitor rapamycin's effects on tumor and T cells in patients undergoing cystectomy.
• Utilized MB49 syngeneic murine bladder cancer models for mechanistic studies.
• Measured rapamycin concentrations in bladder tissue and blood, and assessed T-cell exhaustion markers (PD-1) and mTORC1 activity (rpS6 phosphorylation).

Main Results:

• Rapamycin concentrations were higher in bladder tissue than blood at 3 mg daily oral dose.
• Rapamycin significantly inhibited tumor mTORC1 activity (decreased rpS6 phosphorylation, P = 0.008).
• Rapamycin reduced surgery-induced T-cell exhaustion, decreasing dysfunctional PD-1-expressing T cells.
• Wound complication rates were higher in rapamycin-treated patients, but severe adverse events were similar.

Conclusions:

• Surgery promotes bladder cancer metastasis and diminishes the efficacy of postoperative immunotherapy.
• Low-dose oral rapamycin demonstrates favorable pharmacodynamic and immune-modulating activity in surgical bladder cancer patients.
• Rapamycin has potential to mitigate surgery-induced immune dysfunction and improve outcomes in bladder cancer patients.