Enhancing direct cytotoxicity and response to immune checkpoint blockade following ionizing radiation with Wee1 kinase inhibition

Priya Patel, Lily Sun, Yvette Robbins, Paul E. Clavijo, Jay Friedman, Christopher Silvin, Carter Van Waes, John Cook, James Mitchell, Clint Allen

Research output: Contribution to journalArticle

Abstract

Tumor cells activate the G2/M cell cycle checkpoint in response to ionizing radiation (IR) and effector immune cell-derived granzyme B to facilitate repair and survival. Wee1 kinase inhibition reverses the ability of tumor cells to pause at G2/M. Here, we hypothesized that AZD1775, a small molecule inhibitor of Wee1 kinase, could sensitize tumor cells to IR and T-lymphocyte killing and improve responses to combination IR and programmed death (PD)-axis immune checkpoint blockade (ICB). Multiple models of head and neck carcinoma, lung carcinoma and melanoma were used in vitro and in vivo to explore this hypothesis. AZD1775 reversed G2/M cell cycle checkpoint activation following IR, inducing cell death. Combination IR and AZD1775 induced accumulation of DNA damage in M-phase cells and was rescued with nucleoside supplementation, indicating mitotic catastrophe. Combination treatment enhanced control of syngeneic MOC1 tumors in vivo, and on-target effects of systemic AZD1775 could be localized with targeted IR. Combination treatment enhanced granzyme B-dependent T-lymphocyte killing through reversal of additive G2/M cell cycle block induced by IR and granzyme B. Combination IR and AZ1775-enhanced CD8+ cell-dependent MOC1 tumor growth control and rate of complete rejection of established tumors in the setting of PD-axis ICB. Functional assays demonstrated increased tumor antigen-specific immune responses in sorted T-lymphocytes. The combination of IR and AZD1775 not only lead to enhanced tumor-specific cytotoxicity, it also enhanced susceptibility to T-lymphocyte killing and responses to PD-axis ICB. These data provide the pre-clinical rationale for the combination of these therapies in the clinical trial setting.

Original languageEnglish (US)
Article numbere1638207
JournalOncoImmunology
Volume8
Issue number11
DOIs
StatePublished - Nov 2 2019

Keywords

  • AZD1775
  • G2/M block
  • PD-1 immune checkpoint blockade
  • WEE1 kinase
  • cell cycle
  • cytotoxic T lymphocyte
  • ionizing radiation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

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  • Cite this

    Patel, P., Sun, L., Robbins, Y., Clavijo, P. E., Friedman, J., Silvin, C., Van Waes, C., Cook, J., Mitchell, J., & Allen, C. (2019). Enhancing direct cytotoxicity and response to immune checkpoint blockade following ionizing radiation with Wee1 kinase inhibition. OncoImmunology, 8(11), [e1638207]. https://doi.org/10.1080/2162402X.2019.1638207