Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease

Khaled, M. L.; Ren, Y.; Kundalia, R.; Alhaddad, H.; Chen, Z.; Wallace, G. C.; Evernden, B.; Ospina, O. E.; Hall, M.; Liu, M.; Darville, L. N. F.; Izumi, V.; Chen, Y. A.; Pilon-Thomas, S.; Stewart, P. A.; Koomen, J. M.; Corallo, S. A.; Jain, M. D.; Robinson, T. J.; Locke, F. L.; Forsyth, P. A.; Smalley, I.

doi:10.1101/2023.12.18.572239

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bioRxiv · 10.1101/2023.12.18.572239

Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease

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Abstract

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.

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Khaled, M. L., Ren, Y., Kundalia, R., Alhaddad, H., Chen, Z., Wallace, G. C., Evernden, B., Ospina, O. E., Hall, M., Liu, M., Darville, L. N. F., Izumi, V., Chen, Y. A., Pilon-Thomas, S., Stewart, P. A., Koomen, J. M., Corallo, S. A., Jain, M. D., Robinson, T. J., Locke, F. L., Forsyth, P. A., Smalley, I.. 2023-12-18. Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease. https://doi.org/10.1101/2023.12.18.572239

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