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.

Pan-cancer analysis of ABCC1 as a potential prognostic and immunological biomarker

“…Because of their regulatory effect on immune cells within the tumor microenvironment, immune checkpoint blockade (ICB) proteins have become a promising target for cancer immunotherapy [ 25 , 26 ]. Consequently, we delved into the potential correlation between the expression of immune checkpoint (ICP) genes and ABCC1 across various cancers.…”

Unlocking Glioblastoma Vulnerabilities with CRISPR-Based Genetic Screening

“…CRISPR-based genetic screening has significantly advanced our understanding of GBM vulnerability, leading to the identification of potential new targets and corresponding drugs for GBM treatment, such as DOT1L inhibitor EPZ-5676 [44] and Check1/2 inhibitor Prexasertib [71,74] (Table 1). However, several challenges remain to be addressed in future development.…”

“…The second study by Dmello et al focused on the GBM response to CD8 + T cells [ 71 ]. They conducted an in vivo CRISPRn screen targeting 713 kinases in a xenograft glioma model in WT and CD8 + KO mice.…”

CHEK2 is a potential prognostic biomarker associated with immune infiltration in clear cell renal cell carcinoma

“…Although ICIs can provide a long-term benefit in responders, most people still exhibit ICIs resistance, and it is unclear how immune cells and cancer interact causally 47 . Based on findings from several relevant articles, the application of CHEK2 inhibitors in tumors with high CHEK2 expression can sensitize the tumors to ICIs 48 , 49 . Herein, TIDE scores of all cases in both groups were determined, and it was observed that the group with high CHEK2 expression showed increased TIDE scores, suggesting that this group was less effective for immunotherapy.…”