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Buoyant mass reveals distinct T cell states predictive of checkpoint response

Yu, J.; Zhang, Y.; Duquette, S. M.; Kimmerling, R. J.; Kostas, J. C.; Lum, K. K.; LaBella, R.; Olcum, S.; Vacha, M.; Wasserman, S. C.; Aikins, R.; Katsis, K.; Usherwood, T. R.; Cohen, S.; Dinter, T.; Lawless, A.; Sharova, T.; Stevens, M.; Yee, G. L.; Wu, W.; Spranger, S.; Miettinen, T.; Ileana M Cristea, I. M.; Boland, G. M.; Manalis, S. R.

2025-11-20 biophysics
10.1101/2024.09.26.615179 bioRxiv
Show abstract

T cells are central to immune defense, yet existing molecular and phenotypic assays do not fully capture a cells intrinsic immune potential. Here we show that a single physical property, buoyant mass, reveals hidden heterogeneity within phenotypically similar, resting CD8+ T cells. Using suspended microchannel resonator measurements, we identify two distinct populations: "light" cells, enriched for mitochondrial content but prone to delayed activation and exhaustion, and "heavy" cells, biosynthetically poised for proliferation and memory formation. In patients with melanoma receiving immune checkpoint blockade, pre-treatment buoyant mass profiling of circulating T cells predicted therapeutic response with an accuracy comparable with standard tumor-derived biomarkers. Our findings establish buoyant mass as a label-free, stimulation-independent measure of systemic T cell fitness, providing a rapid and broadly applicable framework for immune profiling and response prediction in cancer and beyond.

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