Kwang‐Soo Kim, Junyi Zhang, Víctor A. Arrieta, Crismita Dmello, Elena Grabis, Y Yabo, Si Wang, Karl Habashy, J. A. Duffy, Junfei Zhao, Andrew Gould, Rishi Jain, Li Chen, Jian Hu, Irina Balyasnikova, Dhan Chand, Daniel Levey, Peter Canoll, Wenting Zhao, Peter A. Sims, Raúl Rabadán, Surya Pandey, Bin Zhang, Pouya Jamshidi, Catalina Lee-Chang, Dieter Henrik Heiland, Adam M. Sonabend
Abstract Glioblastoma (GBM) remains a formidable challenge in neuro-oncology, with immune checkpoint blockade (ICB) only showing efficacy in some patients, while the mechanisms governing therapeutic responsiveness are poorly defined. Although MAPK/ERK signaling correlates with survival following ICB, its causal role and mechanisms underlying tumor immunogenicity remain unclear. Here, we perform in vivo kinome-wide CRISPR/Cas9 screens in murine gliomas where we identify RAF-MEK-ERK axis as the strongest modulators of glioma susceptibility to anti-programmed cell death protein 1 (anti-PD-1) therapy and CD8 + T cell recognition. Experimentally-induced ERK phosphorylation (p-ERK) enhances survival after anti-PD-1 and anti-CTLA-4 therapy, leading to durable antitumor immunity upon rechallenge. Additionally, glioma cell p-ERK promotes increased interferon responses and T cell infiltration. Notably, BRAF/MEK inhibition disrupts interferon programs and tumor-microglia interactions in BRAF V600E ex vivo in human GBM/brain slice cultures. Our findings elucidate that tumor-intrinsic MAPK/ERK promotes immunotherapy response, interferon responses, T cell tumor infiltration, and GBM cell-microglia interactions.