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RIPK1-mediated immunogenic cell death promotes anti-tumour immunity against soft-tissue sarcoma

Henry G Smith1, Kunzah Jamal2, Jasbani Hs Dayal3

  • 1Targeted Therapy Team, The Institute of Cancer Research, London, UK.

EMBO Molecular Medicine
|May 19, 2020
PubMed

Insights

This study shows that activating receptor-interacting serine/threonine-protein kinase 1 (RIPK1) can trigger cancer cell death that alerts the immune system. This RIPK1-mediated cell death improved sarcoma treatment and immune response in pre-clinical models.

Area of Science:

  • Oncology
  • Immunology
  • Cell Death Research

Background:

  • Cancer immunotherapy has advanced significantly, but resistance to apoptosis remains a challenge.
  • Immunogenic cell death (ICD) is crucial for mobilizing anti-tumour immunity, yet not all cell death pathways are immunogenic.
  • Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) activation can induce a form of cell death with immunogenic potential.

Purpose of the Study:

  • To investigate the pre-clinical efficacy of a novel in vivo treatment protocol targeting RIPK1-mediated immunogenic cell death.
  • To evaluate the impact of RIPK1-induced cell death on local disease control and immune cell activation in soft-tissue sarcoma.
  • To determine if RIPK1-mediated cell death can enhance the effectiveness of immune checkpoint blockade therapy.

Main Methods:

  • Development and application of an in vivo treatment protocol to induce RIPK1-mediated cell death in a soft-tissue sarcoma model.
  • Assessment of local disease control and survival benefits post-treatment.
  • Analysis of immune cell activation, including CD8+ T cells and NK cells, and its synergy with immune checkpoint blockade.

Main Results:

  • RIPK1-mediated cell death significantly improved local disease control in soft-tissue sarcoma models.
  • Treatment led to increased activation of cytotoxic CD8+ T cells and natural killer (NK) cells.
  • The combination of RIPK1-induced cell death and immune checkpoint blockade demonstrated enhanced survival benefits.

Conclusions:

  • RIPK1-mediated immunogenic cell death represents a promising therapeutic strategy for soft-tissue sarcoma.
  • The findings support the potential of RIPK1 activation to enhance anti-tumour immunity and improve responses to immunotherapy.
  • A clinical trial is warranted to assess the survival benefit of RIPK1-induced cell death in patients with advanced soft-tissue sarcoma.
Keywords:
RIPK1SMAC mimeticsTNFapoptosissoft-tissue sarcoma

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