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A Senescence-Mimicking (Senomimetic) VEGFR TKI Side Effect Primes Tumor Immune Responses via IFN/STING Signaling

Melissa Dolan1, Yuhao Shi1, Michalis Mastri2

  • 1Department of Experimental Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

Molecular Cancer Therapeutics
|May 1, 2024
PubMed

Insights

Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) can induce cellular senescence, enhancing anti-tumor immunity. This senomimetic effect primes tumors for improved immunotherapy response, particularly with PD-L1 blockade.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptors (VEGFRs) inhibit tumor angiogenesis but cause unexpected side effects.
  • These side effects include inducing senescence markers (SMs) in tumor cells, activating secretory programs that promote drug resistance.
  • VEGFR TKIs can hijack cellular aging programs, leading to 'senomimetic' effects that influence tumor cell behavior and immune signaling.

Purpose of the Study:

  • To investigate how senomimetic effects of VEGFR TKIs impact tumor immunogenicity and response to immunotherapy.
  • To elucidate the role of the STimulator of INterferon Gene (STING) pathway in TKI-induced immune signaling.
  • To determine if senomimetic VEGFR TKI effects can enhance sensitivity to PD-L1 inhibition.

Main Methods:

  • Utilized live-cell sorting based on beta-galactosidase activity to identify senescence marker-expressing (SM+) tumor cell subpopulations.
  • Measured interferon (IFN) signaling and IFN-stimulated gene (ISG) expression in SM+ cells.
  • Assessed the activation of the STimulator of INterferon Gene (STING) pathway and its direct activation by VEGFR TKIs.
  • Evaluated CD8 T-cell activation by TKI-induced SM+ cells in vitro and tumor sensitivity to PD-L1 inhibition in vivo.

Main Results:

  • Subpopulations of SM+ tumor cells exhibit heightened IFN signaling and increased ISG expression, controlled by the STING pathway.
  • Several VEGFR TKIs directly activate the STING pathway.
  • TKI-induced SM+ cells can modulate CD8 T-cell activation, and tumors derived from SM+ cells show increased sensitivity to PD-L1 inhibition.
  • The senomimetic effects of VEGFR TKIs can enhance tumor sensitivity to immunotherapy.

Conclusions:

  • Senomimetic VEGFR TKI effects promote immunogenic signaling via the STING pathway, altering tumor response to immunotherapy.
  • Exploiting these senomimetic side effects may identify TKIs that synergize with PD-L1 targeted agents.
  • This provides a rationale for combining specific VEGFR TKIs with immunotherapy to improve treatment efficacy.

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