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Macrophages directly kill bladder cancer cells through TNF signaling as an early response to BCG therapy

Mayra Fernanda Martínez-López1, Cátia Rebelo de Almeida2, Márcia Fontes2

  • 1Cancer Research Group (CRG), Faculty of Medicine, Universidad de las Américas, Quito 170124, Ecuador.

Disease Models & Mechanisms
|August 8, 2024
PubMed

Insights

The Bacillus Calmette-Guérin (BCG) vaccine triggers early tumor clearance by activating macrophages. These immune cells directly induce cancer cell death, independent of adaptive immunity, revealing a key mechanism of this immunotherapy.

Area of Science:

  • Immunology
  • Oncology
  • Cancer Research

Background:

  • The Bacillus Calmette-Guérin (BCG) vaccine is a long-standing immunotherapy for cancer.
  • Its precise early mechanisms of action, particularly at the cellular level, are not fully understood.

Purpose of the Study:

  • To elucidate the earliest cellular mechanisms driving BCG-induced tumor clearance.
  • To investigate the role of innate immunity in BCG immunotherapy using a novel preclinical model.

Main Methods:

  • Development of a rapid in vivo zebrafish xenograft assay for real-time, single-cell resolution imaging.
  • Observation of interactions between bladder cancer cells, BCG, and innate immune cells.
  • Analysis of macrophage recruitment, polarization, and cytokine induction (TNFa, IL1b, IL6).

Main Results:

  • BCG induced macrophage recruitment and pro-inflammatory polarization within the tumor microenvironment.
  • Macrophages directly triggered cancer cell apoptosis via tumor necrosis factor (TNF) signaling.
  • Depletion of macrophages abolished the BCG-induced anti-tumor effects, highlighting their critical role.

Conclusions:

  • Macrophages alone can induce tumor apoptosis and clearance, challenging the notion that adaptive immunity is solely responsible for this effect.
  • This study reveals an additional mechanism in BCG-induced tumor immunity.
  • The zebrafish model is validated for testing innate immunomodulators in cancer therapy.
Keywords:
BCG immunotherapyBladder cancerInnate immunityMacrophagesTNF signalingZebrafish xenografts

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