Cytotoxic lymphocytes use mechanosurveillance to target biophysical vulnerabilities in cancer

Abstract

33 34 Immune cells identify cancer cells by recognizing characteristic biochemical 35 features indicative of oncogenic transformation. Cancer cells have characteristic 36 mechanical features, as well, but whether these biophysical properties also contribute to 37 destruction by the immune system is not known. In the present study, we found that 38 enhanced expression of myocardin related transcription factors (MRTFs), which promote 39 migration and metastatic invasion, paradoxically compromised lung colonization by 40 melanoma and breast carcinoma cells in an immune-mediated manner. Cancer cells with 41 increased MRTF signaling were also more sensitive to immune checkpoint blockade 42 therapy in mice and humans. The basis for this vulnerability was not biochemical, but 43 biophysical. MRTF expression strengthened the actin cytoskeleton, increasing the 44 rigidity of cancer cells and thereby making them more vulnerable to cytotoxic T 45 lymphocytes and natural killer cells. These results reveal a mechanical dimension of 46 immunosurveillance, which we call mechanosurveillance, that is particularly relevant to 47 109 cytoskeletal components. Morphoregulation by MRTF is absolutely required for metastatic 110 invasion and subsequent proliferative expansion (Er et al., 2018). However, because analogous 111 shape changes have been shown to increase cell stifffness (Kasza et al., 2009), it is tempting to 112 speculate that MRTF signaling might also mechanically sensitize cancer cells to cytotoxic 113 lymphocytes. 114In the present study, we explored this hypothesis by analyzing the effects of MRTF on 115 the mechanical properties of cancer cells, their immune sensitivity, and their capacity to colonize 116 tissues in vivo. Our results reveal a novel, mechanical form of immunosurveillance that enables 117 cytotoxic lymphocytes to target the specific biophysical features of metastatic cancer cells. 118 119 120 5 RESULTS 121 122 MRTF overexpression sensitizes metastatic cells to the immune system 123 Given the importance of MRTF-mediated mechanotransduction for migration and 124 metastasis, and the unique position of MRTF in F-actin regulation, we reasoned that 125 manipulating MRTFA and MRTFB levels might reveal novel vulnerabilities associated with 126 cancer cell architecture (Fig. 1A). To explore this idea, we employed an established model of 127 metastatic colonization in which malignant cancer cells expressing luciferase are injected 128 intravenously into congenic mice and their subsequent growth in the lung monitored by 129 bioluminescent imaging (Fig. 1B). shRNA-mediated suppression of MRTFA and MRTFB130 reduced lung colonization by both B16F10 melanoma and E0771 breast cancer cells in this 131 model (Fig. 1C-D and Fig. S1A), consistent with previous data showing that MRTF is required 132 for metastatic seeding (Er et al., 2018; Kim et al., 2017; Medjkane et al., 2009). However, 133 B16F10 and E0771 cell lines overexpressing MRTFB (B16F10-MRTFB and E0771-MRTFB) 134 exhibited dramatically reduced lung colonization ...

Mouse T cell priming is enhanced by maturation-dependent stiffening of the dendritic cell cortex

“…Although our focus here is on the role of stiffness sensing in priming of naïve T cells, we find that effector CD8 + T cells also exhibit stiffness-dependent degranulation; stiffness-dependent cytokine production by CTLs has also recently been reported ( Tello-Lafoz et al, 2020 ). Similarly, Saitakis et al have shown that restimulating CD4 + effector T cells on surfaces of different stiffness induces differential gene expression and cytokine production ( Saitakis et al, 2017 ).…”

Mechanical Immunoengineering of T cells for Therapeutic Applications

“… Mechanistic studies are required to determine the extent to which stiffness of target cells influences T cell effector functions. More recently, Tello-Lafoz et al discovered that increased cellular stiffness resulting from enhanced expression of myocardin-related transcription factor (MRTF) in metastatic cancer cells enhanced their susceptibility to CTL-mediated killing . Sensing of this biomechanical vulnerability by T cells, a process termed “mechanical immunosurveillance”, offers a novel perspective on the biomechanical nature of T cell immunity, as well as a possible target for mechanical immunoengineering of T cells.…”