Buoyant mass reveals distinct T cell states predictive of checkpoint response

Area of Science:

• Immunology
• Cell Biology
• Biophysics

Background:

• T cells are crucial for immune defense, but current assays fail to fully assess their intrinsic potential.
• Heterogeneity within seemingly similar T cell populations remains largely undetected.
• Understanding T cell fitness is vital for predicting immune responses, especially in cancer.

Purpose of the Study:

• To investigate if a single physical property, buoyant mass, can reveal hidden heterogeneity in T cells.
• To determine the relationship between T cell buoyant mass and their functional potential (activation, proliferation, memory formation).
• To assess the utility of buoyant mass profiling for predicting therapeutic response in cancer patients.

Main Methods:

• Utilized suspended microchannel resonator measurements to determine the buoyant mass of individual resting CD8+ T cells.
• Correlated buoyant mass with cellular properties like mitochondrial content and biosynthetic state.
• Analyzed pre-treatment circulating T cells from melanoma patients undergoing immune checkpoint blockade.

Main Results:

• Identified two distinct T cell populations based on buoyant mass: 'light' (higher mitochondrial content, prone to exhaustion) and 'heavy' (biosynthetically poised for proliferation and memory).
• Buoyant mass profiling of pre-treatment T cells accurately predicted therapeutic response in melanoma patients.
• Prediction accuracy was comparable to established tumor-derived biomarkers.

Conclusions:

• Buoyant mass is a label-free, stimulation-independent physical property that uncovers hidden T cell heterogeneity.
• T cell buoyant mass serves as a reliable indicator of systemic T cell fitness and functional potential.
• Buoyant mass profiling offers a rapid and broadly applicable framework for immune profiling and predicting cancer immunotherapy outcomes.