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

• Published in: Nature communications Vol. 14; no. 1; p. 1566
• Main Authors: Dmello, Crismita, Zhao, Junfei, Chen, Li, Gould, Andrew, Castro, Brandyn, Arrieta, Victor A, Zhang, Daniel Y, Kim, Kwang-Soo, Kanojia, Deepak, Zhang, Peng, Miska, Jason, Yeeravalli, Ragini, Habashy, Karl, Saganty, Ruth, Kang, Seong Jae, Fares, Jawad, Liu, Connor, Dunn, Gavin, Bartom, Elizabeth, Schipma, Matthew J, Hsu, Patrick D, Alghamri, Mahmoud S, Lesniak, Maciej S, Heimberger, Amy B, Rabadan, Raul, Lee-Chang, Catalina, Sonabend, Adam M
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 22.03.2023; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Antigen presentation; Antigens; B7-H1 Antigen; Brain tumors; CD8 antigen; CD8-Positive T-Lymphocytes; Cell activation; Cell recognition; Checkpoint Kinase 1; CHK2 protein; Clinical trials; CRISPR; Depletion; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioma; Glioma - drug therapy; Glioma - genetics; Glioma - pathology; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immune response; Immune system; Immunity; Immunosuppressive agents; Immunotherapy; Kinases; Lymphocytes; Lymphocytes T; Mice; PD-1 protein; PD-L1 protein; Recognition; Survival; Tumor cells; Tumor Microenvironment
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36878-2

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.