Khaled Mariam Lotfy, Ren Yuan, Kundalia Ronak, Alhaddad Hasan, Chen Zhihua, Wallace Gerald C, Evernden Brittany, Ospina Oscar E, Hall MacLean, Liu Min, Darville Lancia N F, Izumi Victoria, Chen Y Ann, Pilon-Thomas Shari, Stewart Paul A, Koomen John M, Corallo Salvatore A, Jain Michael D, Robinson Timothy J, Locke Fredrick L, Forsyth Peter A, Smalley Inna
The Department of Metabolism and Physiology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Department of Biochemistry, Faculty of Pharmacy, Cairo University, Egypt.
bioRxiv. 2023 Dec 18:2023.12.18.572239. doi: 10.1101/2023.12.18.572239.
Leptomeningeal disease (LMD) occurs when tumors seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological deterioration and poor survival outcomes. We utilized comprehensive multi-omics analyses of CSF from patients with lymphoma LMD to demonstrate an immunosuppressive cellular microenvironment and identified dysregulations in proteins and lipids indicating neurodegenerative processes. Strikingly, we found a significant accumulation of toxic branched-chain keto acids (BCKA) in the CSF of patients with LMD. The BCKA accumulation was found to be a pan-cancer occurrence, evident in lymphoma, breast cancer, and melanoma LMD patients. Functionally, BCKA disrupted the viability and function of endogenous T lymphocytes, chimeric antigen receptor (CAR) T cells, neurons, and meningeal cells. Treatment of LMD mice with BCKA-reducing sodium phenylbutyrate significantly improved neurological function, survival outcomes, and efficacy of anti-CD19 CAR T cell therapy. This is the first report of BCKA accumulation in LMD and provides preclinical evidence that targeting these toxic metabolites improves outcomes.
软脑膜疾病（LMD）是指肿瘤播散至软脑膜间隙和脑脊液（CSF）时发生的疾病，可导致严重的神经功能恶化和较差的生存结局。我们对淋巴瘤LMD患者的脑脊液进行了全面的多组学分析，以证明其免疫抑制性细胞微环境，并确定了表明神经退行性变过程的蛋白质和脂质失调。令人惊讶的是，我们发现LMD患者的脑脊液中有毒性支链酮酸（BCKA）显著蓄积。BCKA蓄积在多种癌症中均有发生，在淋巴瘤、乳腺癌和黑色素瘤LMD患者中均很明显。在功能上，BCKA破坏了内源性T淋巴细胞、嵌合抗原受体（CAR）T细胞、神经元和脑膜细胞的活力及功能。用降低BCKA的苯丁酸钠治疗LMD小鼠可显著改善神经功能、生存结局以及抗CD19 CAR T细胞疗法的疗效。这是关于LMD中BCKA蓄积的首次报道，并提供了临床前证据，表明靶向这些有毒代谢产物可改善预后。
