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Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment

Damien Maggiorani1,2, Oanh Le1, Véronique Lisi1

  • 1Centre de recherche du CHU Sainte-Justine, Montréal, QC, Canada.

Nature Communications
|March 19, 2024
PubMed

Insights

Senescent cells impair cancer immunotherapy efficacy. Eliminating these cells restores immune function and improves treatment outcomes, suggesting senolytic drugs could enhance immune checkpoint inhibitors.

Area of Science:

  • Oncology
  • Immunology
  • Cellular Biology

Background:

  • Immune checkpoint inhibitors (ICIs) show promise in cancer treatment but can be limited by impaired immune cell function.
  • Accumulation of senescent cells, particularly therapy-induced senescence (TIS), compromises the effectiveness of cancer immunotherapies.

Purpose of the Study:

  • To investigate the impact of senescent cells on cancer immunotherapy efficacy.
  • To explore the potential of senolytic drugs to overcome immunotherapy resistance.

Main Methods:

  • Studies were conducted in mice with accumulated senescent cells and in models of therapy-induced senescence (TIS).
  • Single-cell transcriptomic analysis was used to examine the tumor micro-environment (TME).
  • The senolytic drug ABT263 (Navitoclax) was administered, and its effects on myeloid cells and CD8 T cells were assessed.

Main Results:

  • Resistance to immunotherapy correlated with reduced CD8 T cell accumulation and activation in tumors.
  • Elimination of senescent cells restored immune homeostasis in the TME and improved survival in mice receiving immunotherapy.
  • ABT263 treatment reversed the immunosuppressive profile of myeloid cells and restored CD8 T cell proliferation.

Conclusions:

  • Senescent cell accumulation compromises cancer immunotherapy effectiveness by impairing CD8 T cell responses.
  • Eliminating senescent cells, potentially with senolytic drugs like ABT263, can restore anti-tumor immunity.
  • Pre-treatment with senolytic drugs before ICIs may represent a novel strategy to enhance cancer immunotherapy outcomes.

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