Pillet, C. | bioRxiv Science

bioRxiv2023

Microenvironment of metastatic site reveals key predictors of PD-1 blockade response in renal cell carcinoma

Immune checkpoint blockade (ICB) therapies have improved the overall survival (OS) of many patients with advanced cancers. However, the response rate to ICB varies widely among patients, exposing non-responders to potentially severe immune-related adverse events. The discovery of new biomarkers to identify patients responding to ICB is now a critical need in the clinic. We therefore investigated the tumor microenvironment (TME) of advanced clear cell renal cell carcinoma (ccRCC) samples from primary and metastatic sites to identify molecular and cellular markers of response to ICB. We revealed a significant discrepancy in treatment response between subgroups based on cell fractions inferred from metastatic sites. One of the subgroups was enriched in non-responders and harbored a lower fraction of CD8+ T cells and plasma cells, as well as a decreased expression of immunoglobulin genes. In addition, we developed the Tumor-Immunity Differential (TID) score which combines features from tumor cells and the TME to accurately predict response to anti-PD-1 immunotherapy (AUC-ROC=0.88, log-rank tests for PFS P < 0.0001, OS P = 0.01). Finally, we also defined TID-related genes (YWHAE, CXCR6 and BTF3), among which YWHAE was validated as a robust predictive marker of ICB response in independent cohorts of pre- or on-treatment biopsies of melanoma and lung cancers. Overall, these results provide a rationale to further explore variations in the cell composition of metastatic sites, and underlying gene signatures, to predict patient response to ICB treatments. One Sentence SummaryTumor microenvironment balance of metastasis and associated genes are key predictors of immunotherapy patient response in kidney cancer.

bioinformatics↗

bioRxiv2022

AB668, a novel highly selective protein kinase CK2 inhibitor with a distinct anti-tumor mechanism as compared to CX-4945 and SGC-CK2-1

Although the involvement of protein kinase CK2 in cancer is well-documented, there is a need for selective CK2 inhibitors suitable for investigating CK2 specific roles in cancer-related biological pathways and further explore its therapeutic potential. Here we have discovered AB668, a new bivalent inhibitor that binds both at the ATP site and an allosteric D pocket unique to CK2. The molecule inhibits CK2 activity with an outstanding selectivity over other kinases. Using caspase activation assay, live-cell imaging and transcriptomic analysis, we have compared the effects of this bivalent inhibitor to the non-selective ATP-competitive inhibitor CX-4945 that reached clinic and to the selective ATP-competitive SGC-CK2-1 molecule. Our results show that in contrast to CX-4945 or SGC-CK2-1, AB668 has a distinct mechanism of action regarding its anti-cancer activity, inducing apoptotic cell death and stimulating distinct biological pathways in several cancer cell lines while sparing healthy cells. Our data suggest that targeting a cryptic CK2 D pocket validates an allosteric approach to targeting CK2 and provides a starting point for creating drug-like CK2 inhibitors for aggressive cancers.

biochemistry↗