Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Microbiology and Molecular Biology, Brigham Young University, UT, Provo, USA.
Oncogene. 2023 Jun;42(25):2088-2098. doi: 10.1038/s41388-023-02713-7. Epub 2023 May 9.
The promise of adaptive cancer immunotherapy in treating highly malignant tumors such as glioblastoma multiforme (GBM) can only be realized through expanding its benefits to more patients. Alleviating various modes of immune suppression has so far failed to achieve such expansion, but exploiting endogenous immune enhancers among mutated cancer genes could represent a more direct approach to immunotherapy improvement. We found that Isocitrate Dehydrogenase-1 (IDH1), which is commonly mutated in gliomas, enhances glioma vaccine efficacy in mice and discerns long from short survivors after vaccine therapy in GBM patients. Extracellular IDH1 directly enhanced T cell responses to multiple tumor antigens, and prolonged experimental glioma cell lysis. Moreover, IDH1 specifically bound to and exhibited sialidase activity against CD8. By contrast, mutant IDH1R132H lacked sialidase activity, delayed killing in glioma cells, and decreased host survival after immunotherapy. Overall, our findings identify IDH1 as an immunotherapeutic enhancer that mediates the known T cell-enhancing reaction of CD8 desialylation. This uncovers a new axis for immunotherapeutic improvement in GBM and other cancers, reveals novel physiological and molecular functions of IDH1, and hints at an unexpectedly direct link between lytic T cell function and metabolic activity in target cells.
在治疗高度恶性肿瘤（如多形性胶质母细胞瘤[GBM]）方面，适应性癌症免疫疗法的前景非常广阔，但要将其益处扩展到更多患者，仍面临诸多挑战。迄今为止，减轻各种免疫抑制模式的方法尚未实现这种扩展，但利用突变型癌症基因中的内源性免疫增强剂可能代表了一种更直接的免疫疗法改善途径。我们发现，在神经胶质瘤中常见突变的异柠檬酸脱氢酶-1（IDH1）可增强小鼠的胶质瘤疫苗疗效，并可区分 GBM 患者接受疫苗治疗后的长期和短期存活者。细胞外 IDH1 可直接增强 T 细胞对多种肿瘤抗原的反应，并延长实验性神经胶质瘤细胞的溶解时间。此外，IDH1 特异性结合 CD8 并表现出唾液酸酶活性。相比之下，突变型 IDH1R132H 缺乏唾液酸酶活性，延迟了神经胶质瘤细胞的杀伤作用，并降低了免疫治疗后的宿主存活率。总的来说，我们的研究结果表明 IDH1 是一种免疫治疗增强剂，介导 CD8 去唾液酸化的已知 T 细胞增强反应。这为 GBM 和其他癌症的免疫治疗改善提供了新的思路，揭示了 IDH1 的新的生理和分子功能，并暗示了溶细胞 T 细胞功能与靶细胞代谢活性之间存在出人意料的直接联系。
