肿瘤细胞治疗研究
英文原题：Glioma-intrinsic MAPK/ERK signaling promotes immunotherapy efficacy through T cell infiltration and interferon responses.
胶质母细胞瘤（GBM）在神经肿瘤学中仍然是一项艰巨的挑战，免疫检查点阻断（ICB）仅对部分患者显示出疗效，而调控治疗反应性的机制尚不明确。
胶质母细胞瘤（GBM）在神经肿瘤学中仍然是一个巨大的挑战，免疫检查点阻断（ICB）仅对部分患者显示出疗效，而调控治疗反应性的机制尚不明确。尽管MAPK/ERK信号传导与ICB后的生存相关，但其因果作用及肿瘤免疫原性背后的机制仍不清楚。在此，我们在小鼠胶质瘤中进行了体内全激酶组CRISPR/Cas9筛选，鉴定出RAF-MEK-ERK轴是胶质瘤对抗程序性细胞死亡蛋白1（anti-PD-1）治疗及CD8+ T细胞识别易感性的最强调控因子。实验性诱导的ERK磷酸化（p-ERK）增强了anti-PD-1和anti-CTLA-4治疗后的生存，并在再次攻击时产生持久的抗肿瘤免疫。此外，胶质瘤细胞p-ERK促进干扰素反应增强和T细胞浸润。值得注意的是，在BRAF V600E人GBM/脑切片培养物的离体实验中，BRAF/MEK抑制破坏了干扰素程序及肿瘤-微胶质细胞相互作用。我们的发现阐明了肿瘤内在的MAPK/ERK促进免疫治疗反应、干扰素反应、T细胞肿瘤浸润及GBM细胞-微胶质细胞相互作用。
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.
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