Checkpoint kinase 1/2 inhibition potentiates anti-tumoral immune response and sensitizes gliomas to immune checkpoint blockade

Crismita Dmello (), Junfei Zhao, Li Chen, Andrew Gould, Brandyn Castro, Victor A. Arrieta, Daniel Y. Zhang, Kwang-Soo Kim, Deepak Kanojia, Peng Zhang, Jason Miska, Ragini Yeeravalli, Karl Habashy, Ruth Saganty, Seong Jae Kang, Jawad Fares, Connor Liu, Gavin Dunn, Elizabeth Bartom, Matthew J. Schipma, Patrick D. Hsu, Mahmoud S. Alghamri, Maciej S. Lesniak, Amy B. Heimberger, Raul Rabadan, Catalina Lee-Chang () and Adam M. Sonabend ()
Additional contact information
Crismita Dmello: Feinberg School of Medicine, Northwestern University
Junfei Zhao: Columbia University
Li Chen: Feinberg School of Medicine, Northwestern University
Andrew Gould: Feinberg School of Medicine, Northwestern University
Brandyn Castro: Feinberg School of Medicine, Northwestern University
Victor A. Arrieta: Feinberg School of Medicine, Northwestern University
Daniel Y. Zhang: Feinberg School of Medicine, Northwestern University
Kwang-Soo Kim: Feinberg School of Medicine, Northwestern University
Deepak Kanojia: Feinberg School of Medicine, Northwestern University
Peng Zhang: Feinberg School of Medicine, Northwestern University
Jason Miska: Feinberg School of Medicine, Northwestern University
Ragini Yeeravalli: Feinberg School of Medicine, Northwestern University
Karl Habashy: Feinberg School of Medicine, Northwestern University
Ruth Saganty: Feinberg School of Medicine, Northwestern University
Seong Jae Kang: Feinberg School of Medicine, Northwestern University
Jawad Fares: Feinberg School of Medicine, Northwestern University
Connor Liu: Washington University School of Medicine
Gavin Dunn: Washington University School of Medicine
Elizabeth Bartom: Northwestern University
Matthew J. Schipma: Northwestern University
Patrick D. Hsu: University of California, Berkeley
Mahmoud S. Alghamri: University of Michigan Medical School
Maciej S. Lesniak: Feinberg School of Medicine, Northwestern University
Amy B. Heimberger: Feinberg School of Medicine, Northwestern University
Raul Rabadan: Columbia University
Catalina Lee-Chang: Feinberg School of Medicine, Northwestern University
Adam M. Sonabend: Feinberg School of Medicine, Northwestern University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Whereas the contribution of tumor microenvironment to the profound immune suppression of glioblastoma (GBM) is clear, tumor-cell intrinsic mechanisms that regulate resistance to CD8 T cell mediated killing are less understood. Kinases are potentially druggable targets that drive tumor progression and might influence immune response. Here, we perform an in vivo CRISPR screen to identify glioma intrinsic kinases that contribute to evasion of tumor cells from CD8 T cell recognition. The screen reveals checkpoint kinase 2 (Chek2) to be the most important kinase contributing to escape from CD8 T-cell recognition. Genetic depletion or pharmacological inhibition of Chek2 with blood-brain-barrier permeable drugs that are currently being evaluated in clinical trials, in combination with PD-1 or PD-L1 blockade, lead to survival benefit in multiple preclinical glioma models. Mechanistically, loss of Chek2 enhances antigen presentation, STING pathway activation and PD-L1 expression in mouse gliomas. Analysis of human GBMs demonstrates that Chek2 expression is inversely associated with antigen presentation and T-cell activation. Collectively, these results support Chek2 as a promising target for enhancement of response to immune checkpoint blockade therapy in GBM.

Date: 2023
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DOI: 10.1038/s41467-023-36878-2

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