학술논문
LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity
Document Type
Original Paper
Author
Krishnamurty, Akshay T.; Shyer, Justin A.; Thai, Minh; Gandham, Vineela; Buechler, Matthew B.; Yang, Yeqing Angela; Pradhan, Rachana N.; Wang, Amber W.; Sanchez, Patricia L.; Qu, Yan; Breart, Beatrice; Chalouni, Cécile; Dunlap, Debra; Ziai, James; Elstrott, Justin; Zacharias, Neelie; Mao, Weiguang; Rowntree, Rebecca K.; Sadowsky, Jack; Lewis, Gail D.; Pillow, Thomas H.; Nabet, Barzin Y.; Banchereau, Romain; Tam, Lucinda; Caothien, Roger; Bacarro, Natasha; Roose-Girma, Merone; Modrusan, Zora; Mariathasan, Sanjeev; Müller, Sören; Turley, Shannon J.
Source
Nature: International weekly journal of science. 611(7934):148-154
Subject
Language
English
ISSN
0028-0836
1476-4687
1476-4687
Abstract
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.
LRRC15-positive cancer-associated fibroblasts constitute a pivotal axis in tumorigenesis and are potential therapeutic targets to improve responses to immune checkpoint blockade.
LRRC15-positive cancer-associated fibroblasts constitute a pivotal axis in tumorigenesis and are potential therapeutic targets to improve responses to immune checkpoint blockade.