Malignancy and tumour progression are associated with cancer-cell softening. Yet how the biomechanics of cancer cells affects T-cell mediated cytotoxicity and thus the outcomes of adoptive T-cell immunotherapies is unknown. Here, we show that T-cell-mediated cancer-cell killing is hampered for cortically soft cancer cells, whose plasma membrane is enriched with cholesterol, and that cancer-cell stiffening via cholesterol depletion augments T-cell cytotoxicity and enhances the efficacy of adoptive T-cell therapy against solid tumours in mice. We also show that the enhanced cytotoxicity against stiffened cancer cells is mediated by augmented T-cell forces arising from an increased accumulation of filamentous actin at the immunological synapse, and that cancer-cell stiffening has a negligible influence on T-cell-receptor signalling, on the production of cytolytic proteins such as granzyme B, on the secretion of interferon gamma and tumour necrosis factor alpha, and on Fas-receptor–Fas-ligand interactions. Our findings reveal a mechanical immune checkpoint that could be targeted therapeutically to improve the effectiveness of cancer immunotherapies.
Cancer cells enriched with cholesterol in their plasma membrane impair T-cell mediated cytotoxicity, which can be augmented by stiffening the cancer cells via cholesterol depletion, as shown in mouse models of adoptive T-cell therapy.
Advanced in vitro
models called “organ-on-a-chip”
can mimic the specific cellular environment found in various tissues.
Many of these models include a thin, sometimes flexible, membrane
aimed at mimicking the extracellular matrix (ECM) scaffold of in vivo
barriers. These membranes are often made of polydimethylsiloxane (PDMS),
a silicone rubber that poorly mimics the chemical and physical properties
of the basal membrane. However, the ECM and its mechanical properties
play a key role in the homeostasis of a tissue. Here, we report about
biological membranes with a composition and mechanical properties
similar to those found in vivo. Two types of collagen-elastin (CE)
membranes were produced: vitrified and nonvitrified (called “hydrogel
membrane”). Their mechanical properties were characterized
using the bulge test method. The results were compared using atomic
force microscopy (AFM), a standard technique used to evaluate the
Young’s modulus of soft materials at the nanoscale. Our results
show that CE membranes with stiffnesses ranging from several hundred
of kPa down to 1 kPa can be produced by tuning the CE ratio, the production
mode (vitrified or not), and/or certain parameters such as temperature.
The Young’s modulus can easily be determined using the bulge
test. This method is a robust and reproducible to determine membrane
stiffness, even for soft membranes, which are more difficult to assess
by AFM. Assessment of the impact of substrate stiffness on the spread
of human fibroblasts on these surfaces showed that cell spread is
lower on softer surfaces than on stiffer surfaces.
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