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BTK inhibition potentiates anti-PD-L1 treatment in murine melanoma: potential role for MDSC modulation in immunotherapy

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Abstract

Myeloid-derived suppressor cells (MDSC) have been linked to loss of immune effector cell function through a variety of mechanisms such as the generation of reactive oxygen and nitrogen species and the production of inhibitory cytokines. Our group has shown that signaling through Bruton’s tyrosine kinase (BTK) is important for MDSC function. Ibrutinib is an orally administered targeted agent that inhibits BTK activation and is currently used for the treatment of B cell malignancies. Using a syngeneic murine model of melanoma, the effect of BTK inhibition with ibrutinib on the therapeutic response to systemic PD-L1 blockade was studied. BTK was expressed by murine MDSC and their activation was inhibited by ibrutinib. Ibrutinib was not directly cytotoxic to cancer cells in vitro, but it inhibited BTK activation in MDSC and reduced expression of inducible nitric oxide synthase (NOS2) and production of nitric oxide. Ibrutinib treatments decreased the levels of circulating MDSC in vivo and increased the therapeutic efficacy of anti-PD-L1 antibody treatment. Gene expression profiling showed that ibrutinib decreased Cybb (NOX2) signaling, and increased IL-17 signaling (upregulating downstream targets Mmp9, Ptgs2, and S100a8). These results suggest that further exploration of MDSC inhibition could enhance the immunotherapy of advanced melanoma.

Précis

Inhibition of Bruton’s tyrosine kinase, a key enzyme in myeloid cellular function, improves therapeutic response to an anti-PD-L1 antibody in an otherwise fairly resistant murine melanoma model.

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Acknowledgements

SS—NIH T32AI 106704-01A1, CA—NIH 1T32 GM139784-01A1, DS—AUA Urology Care Foundation Research Scholars Award, WEC—NCI UM1CA186712

Funding

National Institutes of Health,T32AI 106704-01A1,1T32 GM139784-01A1,T32AI 106704-01A1,American Urological Association Foundation, Urology Care Foundation Research Scholars Award, National Cancer Institute, UM1CA186712

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Author notes

  1. Steven H. Sun, Colin D. Angell these authors equally contributed to this work.

Authors and Affiliations

  1. James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Steven H. Sun, Colin D. Angell, Himanshu Savardekar, Debasish Sundi, David Abood, Brooke Benner, Mallory J. DiVincenzo, Megan Duggan, Fouad Choueiry, Thomas Mace, Prashant Trikha, Gabriella Lapurga, Courtney Johnson, Catherine Chung, Kari L. Kendra & William E. Carson III

  2. Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Steven H. Sun & William E. Carson III

  3. Department of Urology, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Debasish Sundi

  4. Division of Gastrointestinal Oncology, Department of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Thomas Mace

  5. Department of Biomedical Informatics, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Lianbo Yu & Jing Zhao

  6. Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    Erick J. Carlson & Blake R. Peterson

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Contributions

Conceptualization: SHS, DA, WEC Data Curation: SHS, CDA, HS, DS, DA, BB, MJD, MD, FC, PT, GL, KLK, CC Formal Analysis: SHS, CDA, HS, DS, DA, MD, PT, GL, LY, JZ, CC Funding Acquisition: DS, WEC Investigation: SHS, CDA, HS Methodology: SHS, CDA, HS, WEC Project Administration: WEC Resources: KLK, WEC Supervision: WEC Visualization: SHS, CDA, HS, DA Writing - Original Draft Preparation: SHS, CDA, HS, DS, DA, WEC Writing - Review and Editing: All authors

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Correspondence to William E. Carson III.

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Sun, S.H., Angell, C.D., Savardekar, H. et al. BTK inhibition potentiates anti-PD-L1 treatment in murine melanoma: potential role for MDSC modulation in immunotherapy. Cancer Immunol Immunother 72, 3461–3474 (2023). https://doi.org/10.1007/s00262-023-03497-1

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