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Proteomics of human cancer-associated T cells identifies regulators of T cell functionality

Bresser, K.; Hozjan, Z.; Servaas, N. H.; Stelloo, S.; Spruijt, C. G.; Nestor Martin, M.; Guislain, A.; Kanagasabesan, N.; Kneefel, S.; Hoogendijk, A. J.; van der Zwaan, C.; Moravec, Z.; Voogd, R.; Nieuwland, M.; Sieljes, J.; van Es, R.; Monkhorst, K.; Hartemink, K.; Theelen, W. S.; Scheper, W.; Vermeulen, M.; Wolkers, M. C.

2026-08-23 immunology
10.64898/2026.08.18.745433 bioRxiv
Show abstract

CD8+ T cells in solid cancers progressively lose anti-tumor activity, yet the cell-intrinsic mechanisms driving this loss of function remain incompletely defined. Here, we performed matched proteomic and transcriptomic profiling of dysfunctional and bystander CD8+ tumor-infiltrating T cells isolated from primary tumors of treatment-naive non-small cell lung cancer patients. Proteomic analysis revealed widespread discordance with mRNA expression, with 8% of all quantified proteins displaying differential expression exclusively at the protein level. Genetic perturbation of such differentially expressed proteins identified the chromatin remodeler CHD4 and fatty acid synthase (FASN) as cell-intrinsic regulators of T cell function. CHD4 deletion resulted in altered gene-regulatory networks that promoted effector differentiation and enhanced cytokine production. In contrast, FASN deletion preserved mitochondrial fitness and sustained T cell functionality under chronic T cell receptor stimulation. Together, these findings demonstrate that proteomic profiling uncovers regulators of T cell functionality that are not apparent from transcriptomic analyses alone, highlighting an additional layer of regulatory control.

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