LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity

2022

["Krishnamurty", "Shyer", "Thai", "Gandham", "Buechler", "Yang", "Pradhan", "Wang", "Sanchez", "Qu", "Breart", "Chalouni", "Dunlap", "Ziai", "Elstrott", "Zacharias", "Mao", "Rowntree", "Sadowsky", "Lewis", "Pillow", "Nabet", "Banchereau", "Tam", "Caothien", "Bacarro", "Roose-Girma", "Modrusan", "Mariathasan", "M\u00fcller", "Turley"]

Abstract

jats:titleAbstract</jats:title>jats:pRecent single-cell studies of cancer in both mice and humans have identified the emergence of a myofibroblast population specifically marked by the highly restricted leucine-rich-repeat-containing protein 15 (LRRC15)jats:sup1–3</jats:sup>. However, the molecular signals that underlie the development of LRRC15jats:sup+</jats:sup> cancer-associated fibroblasts (CAFs) and their direct impact on anti-tumour immunity are uncharacterized. Here in mouse models of pancreatic cancer, we provide in vivo genetic evidence that TGFβ receptor type 2 signalling in healthy dermatopontinjats:sup+</jats:sup> universal fibroblasts is essential for the development of cancer-associated LRRC15jats:sup+</jats:sup> myofibroblasts. This axis also predominantly drives fibroblast lineage diversity in human cancers. Using newly developed jats:italicLrrc15–</jats:italic>diphtheria toxin receptor knock-in mice to selectively deplete LRRC15jats:sup+</jats:sup> CAFs, we show that depletion of this population markedly reduces the total tumour fibroblast content. Moreover, the CAF composition is recalibrated towards universal fibroblasts. This relieves direct suppression of tumour-infiltrating CD8jats:sup+</jats:sup> T cells to enhance their effector function and augments tumour regression in response to anti-PDL1 immune checkpoint blockade. Collectively, these findings demonstrate that TGFβ-dependent LRRC15jats:sup+</jats:sup> CAFs dictate the tumour-fibroblast setpoint to promote tumour growth. These cells also directly suppress CD8jats:sup+</jats:sup> T cell function and limit responsiveness to checkpoint blockade. Development of treatments that restore the homeostatic fibroblast setpoint by reducing the population of pro-disease LRRC15jats:sup+</jats:sup> myofibroblasts may improve patient survival and response to immunotherapy.</jats:p>

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