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Targeting MerTK Enhances Adaptive Immune Responses After Radiation Therapy.

Garth W Tormoen1, Tiffany C Blair2, Shelly Bambina3

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International Journal of Radiation Oncology, Biology, Physics
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MerTK inhibition enhances anti-tumor immunity after radiation therapy (RT). Warfarin, an inhibitor of MerTK, improved tumor control and survival in preclinical models and patients with non-small cell lung cancer receiving SABR.

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Area of Science:

  • Oncology
  • Immunology
  • Radiotherapy

Background:

  • The role of MerTK (a receptor tyrosine kinase) in the immune response to radiation therapy (RT) is not well understood.
  • Investigating MerTK's function is crucial for optimizing cancer treatment strategies.

Purpose of the Study:

  • To investigate the role of MerTK in immune-mediated tumor control following RT.
  • To determine if MerTK inhibition with warfarin can mimic the effects of MerTK knockout.
  • To evaluate the impact of MerTK inhibition on adaptive immune responses and patient outcomes.

Main Methods:

  • Utilized MerTK wild-type and knockout murine models of colorectal and pancreatic adenocarcinoma treated with RT.
  • Conducted cell depletion studies to assess the role of macrophages and CD8 T cells.
  • Evaluated MerTK's role in immune priming with RT and OX40 agonist antibodies.
  • Assessed warfarin's effect on in-field and abscopal responses to RT.
  • Retrospectively analyzed patient data on warfarin use and survival after SABR for non-small cell lung cancer.

Main Results:

  • MerTK knockout hosts exhibited improved tumor control post-RT, dependent on macrophages and CD8 T cells.
  • MerTK knockout mice showed increased tumor antigen-specific CD8 T cells after RT, alone or with anti-OX40.
  • Warfarin treatment replicated MerTK knockout phenotypes in RT-treated murine models and enhanced abscopal responses when combined with anti-CTLA4.
  • Patients with non-small cell lung cancer receiving SABR and warfarin had improved progression-free survival.

Conclusions:

  • MerTK signaling suppresses adaptive immune responses to stereotactic ablative radiotherapy (SABR).
  • Warfarin, by inhibiting MerTK, may enhance the efficacy of SABR and immunotherapy combinations.
  • Warfarin holds potential as an adjuvant therapy to improve outcomes for cancer patients undergoing RT.