LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity

Akshay T. Krishnamurty, Justin A. Shyer, Minh Thai, Vineela Gandham, Matthew B. Buechler, Yeqing Angela Yang, Rachana N. Pradhan, Amber W. Wang, Patricia L. Sanchez, Yan Qu, Beatrice Breart, Cécile Chalouni, Debra Dunlap, James Ziai, Justin Elstrott, Neelie Zacharias, Weiguang Mao, Rebecca K. Rowntree, Jack Sadowsky, Gail D. Lewis, Thomas H. Pillow, Barzin Y. Nabet, Romain Banchereau, Lucinda Tam, Roger Caothien, Natasha Bacarro, Merone Roose-Girma, Zora Modrusan, Sanjeev Mariathasan, Sören Müller () and Shannon J. Turley ()
Additional contact information
Akshay T. Krishnamurty: Genentech
Justin A. Shyer: Genentech
Minh Thai: Genentech
Vineela Gandham: Genentech
Matthew B. Buechler: Genentech
Yeqing Angela Yang: Genentech
Rachana N. Pradhan: Genentech
Amber W. Wang: Genentech
Patricia L. Sanchez: Genentech
Yan Qu: Genentech
Beatrice Breart: Genentech
Cécile Chalouni: Genentech
Debra Dunlap: Genentech
James Ziai: Genentech
Justin Elstrott: Genentech
Neelie Zacharias: Genentech
Weiguang Mao: Genentech
Rebecca K. Rowntree: Genentech
Jack Sadowsky: Genentech
Gail D. Lewis: Genentech
Thomas H. Pillow: Genentech
Barzin Y. Nabet: Genentech
Romain Banchereau: Genentech
Lucinda Tam: Genentech
Roger Caothien: Genentech
Natasha Bacarro: Genentech
Merone Roose-Girma: Genentech
Zora Modrusan: Genentech
Sanjeev Mariathasan: Genentech
Sören Müller: Genentech
Shannon J. Turley: Genentech

Nature, 2022, vol. 611, issue 7934, 148-154

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-05272-1

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