WEE1 kinase inhibition reverses G2/M cell cycle checkpoint activation to sensitize cancer cells to immunotherapy

Lillian Sun, Ellen Moore, Rose Berman, Paul E. Clavijo, Anthony Saleh, Zhong Chen, Carter Van Waes, John Davies, Jay Friedman, Clint T Allen

Research output: Contribution to journalArticle

Abstract

Intrinsic resistance to cytotoxic T-lymphocyte (CTL) killing limits responses to immune activating anti-cancer therapies. Here, we established that activation of the G2/M cell cycle checkpoint results in tumor cell cycle pause and protection from granzyme B-induced cell death. This was reversed with WEE1 kinase inhibition, leading to enhanced CTL killing of antigen-positive tumor cells. Similarly, but at a later time point, cell cycle pause following TNFα exposure was reversed with WEE1 kinase inhibition, leading to CTL transmembrane TNFα-dependent induction of apoptosis and necroptosis in bystander antigen-negative tumor cells. Results were reproducible in models of oral cavity carcinoma, melanoma and colon adenocarcinoma harboring variable Tp53 genomic alterations. WEE1 kinase inhibition sensitized tumors to PD-1 mAb immune checkpoint blockade in vivo, resulting in CD8+-dependent rejection of established tumors harboring antigen-positive or mixed antigen-positive and negative tumor cells. Together, these data describe activation of the G2/M cell cycle checkpoint in response to early and late CTL products as a mechanism of resistance to CTL killing, and provide pre-clinical rationale for the clinical combination of agents that inhibit cell cycle checkpoints and activate anti-tumor immunity.

Original languageEnglish (US)
JournalOncoImmunology
DOIs
Publication statusAccepted/In press - Jan 1 2018

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Keywords

  • antigenicity
  • bystander killing
  • checkpoint inhibition
  • intrinsic resistance
  • WEE1 kinase

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

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