LRRC15(+) myofibroblasts dictate the stromal setpoint to suppress tumour immunity
Open accessAbstract
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.
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CD105 identifies two functionally distinct and non-interconvertible CAF populations: tumor-permissive CD105+ CAFs and tumor-suppressive CD105− CAFs.
“single-cell mass cytometric analysis has identified that the cell surface marker CD105 can be used to identify two functionally distinct and non-interconvertible populations of CAFs, namely, tumor permissive CD105+ CAFs, and tumor suppressive CD105− CAFs152”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [152]
Mass cytometry comparing millions of cells from 19 murine PDAC tumors against 40+ fibroblast/mesenchymal markers was integral to discovering CD105 as a key indicator of tumor-promoting/suppressive fibroblast behavior.
“The use of mass cytometry comparing millions of cells isolated from 19 murine PDAC tumors against library of 40+ known fibroblast and mesenchymal cell markers was integral to the discovery of CD105 as a key indicator of tumor promoting/tumor suppressive fibroblast behavior152.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [152]
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- Authors
- Krishnamurty, A. T., Shyer, J. A., Thai, M., Gandham, V., Buechler, M. B., Yang, Y. A., Pradhan, R. N., Wang, A. W., Sanchez, P. L., Qu, Y., Breart, B., Chalouni, C., Dunlap, D., Ziai, J., Elstrott, J., Zacharias, N., Mao, W., Rowntree, R. K., Sadowsky, J., Lewis, G. D., Pillow, T. H., Nabet, B. Y., Banchereau, R., Tam, L., Caothien, R., Bacarro, N., Roose-Girma, M., Modrusan, Z., Mariathasan, S., Müller, S., & Turley, S. J.
- Affiliations
- Genentech (US)
- Corresponding author
- Müller, Sören
- Turley, Shannon J.
- ORCID
- Krishnamurty, Akshay T.
- Shyer, Justin A.
- Gandham, Vineela
- Buechler, Matthew B.
- Yang, Yeqing Angela
- Pradhan, Rachana N.
- Qu, Yan
- Dunlap, Debra
- Ziai, James
- Elstrott, Justin
- Zacharias, Neelie
- Mao, Weiguang
- Rowntree, Rebecca K.
- Sadowsky, Jack
- Pillow, Thomas H.
- Nabet, Barzin Y.
- Banchereau, Romain
- Tam, Lucinda
- Caothien, Roger
- Bacarro, Natasha
- Modrusan, Zora
- Mariathasan, Sanjeev
- Müller, Sören
- Turley, Shannon J.
- Venue
- Nature
- Published
- 2022-09-28
- Volume
- 611
- Issue
- 7934
- Pages
- 148-154
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9630141
- OpenAlex
- W4297497831
- Cited by
- 436
- References
- 35
- Citations by year
- 2026: 144 · 2025: 107 · 2024: 107 · 2023: 71 · 2022: 6 · 2021: 1
- FWCI
- 30.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Amgen
- Bristol-Myers Squibb
- Pfizer
- Genentech
- University of California, San Francisco
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- LRRC15, cancer-associated fibroblasts, myofibroblasts, pancreatic cancer, tumor microenvironment, CD8+ T cell suppression, dermatopontin, fibroblast depletion, tumor immunosuppression
- MeSH terms
- Cancer-Associated Fibroblasts, Animals, Humans, Membrane Proteins, Pancreatic Neoplasms, Transforming Growth Factor beta, Stromal Cells, Receptors, Transforming Growth Factor beta, CD8-Positive T-Lymphocytes, Mice, Myofibroblasts, Tumor Microenvironment, B7-H1 Antigen
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