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bioRxiv · 10.1101/2022.03.04.483014

Loss of the adhesion protein Kindlin-1 stimulates tumor clearance via modulation of Tregs

Webb, E.·Dodd, G.·Bullock, E.·Muir, M.·Frame, M. C.·Serrels, A.·Brunton, V.
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Abstract

The adhesion protein Kindlin-1 is over-expressed in breast cancer where it has been shown to be associated with metastasis-free survival, however, the mechanisms involved are poorly understood. Here, we report that Kindlin-1 promotes anti-tumor immune evasion in a mouse model of breast cancer. Deletion of Kindlin-1 in Met-1 mammary tumor cells leads to tumor regression following injection into immunocompetent hosts. This was associated with a reduction in tumor infiltrating Tregs and impairment of their immune-suppressive activities in Kindlin-1 depleted tumors. Similar changes in T cell populations were seen following depletion of Kindlin-1 in the polyomavirus middle T antigen (PyV MT)-driven mouse model of mammary tumorigenesis. Analysis of cytokines secreted from the Met-1 cells identified a significant increase in IL-6 secretion when Kindlin-1 was depleted. Conditioned media from Kindlin-1 depleted cells lead to a decrease in the ability of Tregs to suppress the proliferation of CD8+ T cells, which was dependent on IL-6 and depletion of CD25+ Tregs resulted in a reduction of Met-1 tumor growth in mice. Overall, these data identify a novel function for Kindlin-1 in the regulation of anti-tumor immunity through cytokine regulation of Treg number and function.

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Webb, E., Dodd, G., Bullock, E., Muir, M., Frame, M. C., Serrels, A., Brunton, V.. 2022-03-05. Loss of the adhesion protein Kindlin-1 stimulates tumor clearance via modulation of Tregs. https://doi.org/10.1101/2022.03.04.483014

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