Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment

Damien Maggiorani, Oanh Le, Véronique Lisi, Séverine Landais, Gaël Moquin-Beaudry, Vincent Philippe Lavallée, Hélène Decaluwe and Christian Beauséjour ()
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Damien Maggiorani: Centre de recherche du CHU Sainte-Justine
Oanh Le: Centre de recherche du CHU Sainte-Justine
Véronique Lisi: Centre de recherche du CHU Sainte-Justine
Séverine Landais: Centre de recherche du CHU Sainte-Justine
Gaël Moquin-Beaudry: Institut Gustave Roussy
Vincent Philippe Lavallée: Centre de recherche du CHU Sainte-Justine
Hélène Decaluwe: Centre de recherche du CHU Sainte-Justine
Christian Beauséjour: Centre de recherche du CHU Sainte-Justine

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract The potential of immune checkpoint inhibitors (ICI) may be limited in situations where immune cell fitness is impaired. Here, we show that the efficacy of cancer immunotherapies is compromised by the accumulation of senescent cells in mice and in the context of therapy-induced senescence (TIS). Resistance to immunotherapy is associated with a decrease in the accumulation and activation of CD8 T cells within tumors. Elimination of senescent cells restores immune homeostasis within the tumor micro-environment (TME) and increases mice survival in response to immunotherapy. Using single-cell transcriptomic analysis, we observe that the injection of ABT263 (Navitoclax) reverses the exacerbated immunosuppressive profile of myeloid cells in the TME. Elimination of these myeloid cells also restores CD8 T cell proliferation in vitro and abrogates immunotherapy resistance in vivo. Overall, our study suggests that the use of senolytic drugs before ICI may constitute a pharmacological approach to improve the effectiveness of cancer immunotherapies.

Date: 2024
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DOI: 10.1038/s41467-024-46769-9

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