LRRC15 + myofibroblasts dictate the stromal setpoint to suppress tumour immunity.

Autor: Krishnamurty AT; Genentech, South San Francisco, CA, USA., Shyer JA; Genentech, South San Francisco, CA, USA., Thai M; Genentech, South San Francisco, CA, USA., Gandham V; Genentech, South San Francisco, CA, USA., Buechler MB; Genentech, South San Francisco, CA, USA., Yang YA; Genentech, South San Francisco, CA, USA., Pradhan RN; Genentech, South San Francisco, CA, USA., Wang AW; Genentech, South San Francisco, CA, USA., Sanchez PL; Genentech, South San Francisco, CA, USA., Qu Y; Genentech, South San Francisco, CA, USA., Breart B; Genentech, South San Francisco, CA, USA., Chalouni C; Genentech, South San Francisco, CA, USA., Dunlap D; Genentech, South San Francisco, CA, USA., Ziai J; Genentech, South San Francisco, CA, USA., Elstrott J; Genentech, South San Francisco, CA, USA., Zacharias N; Genentech, South San Francisco, CA, USA., Mao W; Genentech, South San Francisco, CA, USA., Rowntree RK; Genentech, South San Francisco, CA, USA., Sadowsky J; Genentech, South San Francisco, CA, USA., Lewis GD; Genentech, South San Francisco, CA, USA., Pillow TH; Genentech, South San Francisco, CA, USA., Nabet BY; Genentech, South San Francisco, CA, USA., Banchereau R; Genentech, South San Francisco, CA, USA., Tam L; Genentech, South San Francisco, CA, USA., Caothien R; Genentech, South San Francisco, CA, USA., Bacarro N; Genentech, South San Francisco, CA, USA., Roose-Girma M; Genentech, South San Francisco, CA, USA., Modrusan Z; Genentech, South San Francisco, CA, USA., Mariathasan S; Genentech, South San Francisco, CA, USA., Müller S; Genentech, South San Francisco, CA, USA. Muller.Soren@gene.com., Turley SJ; Genentech, South San Francisco, CA, USA. Turley.Shannon@gene.com.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Nov; Vol. 611 (7934), pp. 148-154. Date of Electronic Publication: 2022 Sep 28.
DOI: 10.1038/s41586-022-05272-1
Abstrakt: Recent 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) 1-3 . However, the molecular signals that underlie the development of LRRC15 + 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 dermatopontin + universal fibroblasts is essential for the development of cancer-associated LRRC15 + myofibroblasts. This axis also predominantly drives fibroblast lineage diversity in human cancers. Using newly developed Lrrc15-diphtheria toxin receptor knock-in mice to selectively deplete LRRC15 + 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 CD8 + 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 LRRC15 + CAFs dictate the tumour-fibroblast setpoint to promote tumour growth. These cells also directly suppress CD8 + 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 LRRC15 + myofibroblasts may improve patient survival and response to immunotherapy.
(© 2022. The Author(s).)
Databáze: MEDLINE
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