Resilient CD8+ T cells maintain a high cytotoxic capacity by balancing ROS via ME1 upregulation

Gicobi, J. K.; Mao, Z.; DeFranco, G.; Li, Y.; Liu, C.; Hirdler, J. B.; Vianzon, V. V.; Dellacecca, E. R.; Hsu, M. A.; Barham, W.; Kim, Y. H.; Feven, A.; Harmsen, W. S.; Yan, Y.; Dronca, R. S.; Zhu, M.; Markovic, S.; Mansfield, A. S.; Lin, Y.; Wu, X.; Owen, D.; Grams, M. P.; Orme, J. J.; Lucien, F.; Zeng, H.; Park, S. S.; Dong, H.

doi:10.1101/2022.11.25.517988

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bioRxiv · 10.1101/2022.11.25.517988

Resilient CD8+ T cells maintain a high cytotoxic capacity by balancing ROS via ME1 upregulation

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Abstract

Cytotoxic T lymphocytes (CTL) are indispensable in anti-tumor immunity. Although CTLs are prone to exhaustion in patients with advanced cancer, T cell resiliency explains the presence of tumor-reactive CTLs that are less exhausted, capable of cytolytic function, expansion, and rebound in response to immunotherapy to reject metastatic malignances. However, the features of resilient T cells have not been clearly defined. In this report, we demonstrate that peripheral CX3CR1+ CD8+ T cells with low mitochondrial membrane potential rebounded CTL function quickly after radiation therapy in patients with large tumor burden portraying their functional resiliency. Furthermore, CX3CR1+ CD8+ T cell with low, but not high, mitochondrial membrane potential are highly cytotoxic, accumulate less reactive oxygen species (ROS), and express more Malic enzyme 1 (ME1). ME1 overexpression increases ATP production in a glycolysisindependent manner while concurrently curtailing excessive ROS in activated CD8+ T cells; and expands CX3CR1+NKG7+ effector CD8+ T cells with enhanced cytotoxicity. Importantly, transfection of ME1 mRNA promotes tumoricidal activity in CD8+ T cells from patients with advanced cancers. Our study reveals a mechanism used by CTLs to balance excessive ROS via ME1 to maintain a metabolic and functional resiliency. Modification of ME1 expression in CTLs may be a novel method to improve the efficacy of cancer immunotherapy by preventing T cell exhaustion. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=191 SRC="FIGDIR/small/517988v3_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@12e0f36org.highwire.dtl.DTLVardef@e8d412org.highwire.dtl.DTLVardef@1baf57eorg.highwire.dtl.DTLVardef@14b2b43_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LICX3CR1+ and low Dy m identify functional resilient CD8+ T cells. C_LIO_LIResilient CD8+ T cells are highly cytotoxic and have less ROS. C_LIO_LIResilient CD8+ T cells express more ME1 that can balance extra ROS. C_LIO_LIME1 overexpression can promote CTL function of CD8+ T cells. C_LI

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Gicobi, J. K., Mao, Z., DeFranco, G., Li, Y., Liu, C., Hirdler, J. B., Vianzon, V. V., Dellacecca, E. R., Hsu, M. A., Barham, W., Kim, Y. H., Feven, A., Harmsen, W. S., Yan, Y., Dronca, R. S., Zhu, M., Markovic, S., Mansfield, A. S., Lin, Y., Wu, X., Owen, D., Grams, M. P., Orme, J. J., Lucien, F., Zeng, H., Park, S. S., Dong, H.. 2022-11-26. Resilient CD8+ T cells maintain a high cytotoxic capacity by balancing ROS via ME1 upregulation. https://doi.org/10.1101/2022.11.25.517988

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