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; Adam M. Sonabend

doi:10.1038/s41467-023-36878-2

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. SchipmaPatrick D. Hsu, Mahmoud S. Alghamri, Maciej S. Lesniak, Amy B. Heimberger, Raul Rabadan, Catalina Lee-Chang^*, Adam M. Sonabend^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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.

Original language	English (US)
Article number	1566
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-36878-2
State	Published - Dec 2023

Funding

This work was funded by the NIH grants 1R01NS110703 (to AMS), 5DP5OD021356 (to A.M.S.), funding support from the Lou and Jean Malnati Brain Tumor Institute (to A.M.S.), and philanthropic support from Dan and Sharon Moceri (to A.M.S.), R01 CA120813 (to A.B.H.), P50CA221747 SPORE for Translational Approaches to Brain Cancer (to ML), DOD Horizon award W81XWH-20-1-0850 Log# CA190063 (to C.D.). We sincerely thank our deceased colleague Joshua Robert Kane for his contributions towards performing experiments and data analyses. The images in Figs. b, a, c, i, a– and Supplementary Figs. , and were created with BioRender.com.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-023-36878-2

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Dmello, C., Zhao, J., Chen, L., Gould, A., Castro, B., Arrieta, V. A., Zhang, D. Y., Kim, K. S., Kanojia, D., Zhang, P., Miska, J., Yeeravalli, R., Habashy, K., Saganty, R., Kang, S. J., Fares, J., Liu, C., Dunn, G., Bartom, E., ... Sonabend, A. M. (2023). Checkpoint kinase 1/2 inhibition potentiates anti-tumoral immune response and sensitizes gliomas to immune checkpoint blockade. Nature communications, 14(1), Article 1566. https://doi.org/10.1038/s41467-023-36878-2

@article{fb98232c78f64331a93b441353ebfed2,

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

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.",

author = "Crismita Dmello and Junfei Zhao and Li Chen and Andrew Gould and Brandyn Castro and Arrieta, {Victor A.} and Zhang, {Daniel Y.} and Kim, {Kwang Soo} and Deepak Kanojia and Peng Zhang and Jason Miska and Ragini Yeeravalli and Karl Habashy and Ruth Saganty and Kang, {Seong Jae} and Jawad Fares and Connor Liu and Gavin Dunn and Elizabeth Bartom and Schipma, {Matthew J.} and Hsu, {Patrick D.} and Alghamri, {Mahmoud S.} and Lesniak, {Maciej S.} and Heimberger, {Amy B.} and Raul Rabadan and Catalina Lee-Chang and Sonabend, {Adam M.}",

note = "Funding Information: This work was funded by the NIH grants 1R01NS110703 (to AMS), 5DP5OD021356 (to A.M.S.), funding support from the Lou and Jean Malnati Brain Tumor Institute (to A.M.S.), and philanthropic support from Dan and Sharon Moceri (to A.M.S.), R01 CA120813 (to A.B.H.), P50CA221747 SPORE for Translational Approaches to Brain Cancer (to ML), DOD Horizon award W81XWH-20-1-0850 Log# CA190063 (to C.D.). We sincerely thank our deceased colleague Joshua Robert Kane for his contributions towards performing experiments and data analyses. The images in Figs. b, a, c, i, a– and Supplementary Figs. , and were created with BioRender.com. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-36878-2",

language = "English (US)",

volume = "14",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Dmello, C, Zhao, J, Chen, L, Gould, A, Castro, B, Arrieta, VA, Zhang, DY, Kim, KS, Kanojia, D, Zhang, P , Miska, J, Yeeravalli, R, Habashy, K, Saganty, R, Kang, SJ, Fares, J, Liu, C, Dunn, G, Bartom, E, Schipma, MJ, Hsu, PD, Alghamri, MS, Lesniak, MS, Heimberger, AB, Rabadan, R, Lee-Chang, C & Sonabend, AM 2023, 'Checkpoint kinase 1/2 inhibition potentiates anti-tumoral immune response and sensitizes gliomas to immune checkpoint blockade', Nature communications, vol. 14, no. 1, 1566. https://doi.org/10.1038/s41467-023-36878-2

TY - JOUR

T1 - Checkpoint kinase 1/2 inhibition potentiates anti-tumoral immune response and sensitizes gliomas to immune checkpoint blockade

AU - Dmello, Crismita

AU - Zhao, Junfei

AU - Chen, Li

AU - Gould, Andrew

AU - Castro, Brandyn

AU - Arrieta, Victor A.

AU - Zhang, Daniel Y.

AU - Kim, Kwang Soo

AU - Kanojia, Deepak

AU - Zhang, Peng

AU - Miska, Jason

AU - Yeeravalli, Ragini

AU - Habashy, Karl

AU - Saganty, Ruth

AU - Kang, Seong Jae

AU - Fares, Jawad

AU - Liu, Connor

AU - Dunn, Gavin

AU - Bartom, Elizabeth

AU - Schipma, Matthew J.

AU - Hsu, Patrick D.

AU - Alghamri, Mahmoud S.

AU - Lesniak, Maciej S.

AU - Heimberger, Amy B.

AU - Rabadan, Raul

AU - Lee-Chang, Catalina

AU - Sonabend, Adam M.

N1 - Funding Information: This work was funded by the NIH grants 1R01NS110703 (to AMS), 5DP5OD021356 (to A.M.S.), funding support from the Lou and Jean Malnati Brain Tumor Institute (to A.M.S.), and philanthropic support from Dan and Sharon Moceri (to A.M.S.), R01 CA120813 (to A.B.H.), P50CA221747 SPORE for Translational Approaches to Brain Cancer (to ML), DOD Horizon award W81XWH-20-1-0850 Log# CA190063 (to C.D.). We sincerely thank our deceased colleague Joshua Robert Kane for his contributions towards performing experiments and data analyses. The images in Figs. b, a, c, i, a– and Supplementary Figs. , and were created with BioRender.com. Publisher Copyright: © 2023, The Author(s).

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-023-36878-2

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SN - 2041-1723

VL - 14

JO - Nature communications

JF - Nature communications

IS - 1

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ER -

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

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