Single-cell RNA sequencing reveals stromal evolution into LRRC15(+) myofibroblasts as a determinant of patient response to cancer immunotherapy
Published version of a preprint
Abstract
With only a fraction of patients responding to cancer immunotherapy, a better understanding of the entire tumor microenvironment is needed. Using single-cell transcriptomics, we chart the fibroblastic landscape during pancreatic ductal adenocarcinoma (PDAC) progression in animal models. We identify a population of carcinoma-associated fibroblasts (CAF) that are programmed by TGFβ and express the leucine-rich repeat containing 15 (LRRC15) protein. These LRRC15+ CAFs surround tumor islets and are absent from normal pancreatic tissue. The presence of LRRC15+ CAFs in human patients was confirmed in >80,000 single cells from 22 patients with PDAC as well as by using IHC on samples from 70 patients. Furthermore, immunotherapy clinical trials comprising more than 600 patients across six cancer types revealed elevated levels of the LRRC15+ CAF signature correlated with poor response to anti–PD-L1 therapy. This work has important implications for targeting nonimmune elements of the tumor microenvironment to boost responses of patients with cancer to immune checkpoint blockade therapy. Significance: This study describes the single-cell landscape of CAFs in pancreatic cancer during in vivo tumor evolution. A TGFβ-driven, LRRC15+ CAF lineage is associated with poor outcome in immunotherapy trial data comprising multiple solid-tumor entities and represents a target for combinatorial therapy. This article is highlighted in the In This Issue feature, p. 161
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apCAFs express several components of the antigen presentation machinery typically found on myeloid populations.
“One population expresses several components of the antigen presentation machinery typically found on myeloid populations.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [149]
Single-cell RNA sequencing of human and murine tumors found several distinct neoplastic epithelial populations in one tumor, corresponding to multiple PDAC subtypes.
“scRNA-seq datasets from human and murine tumors have identified multiple unique neoplastic epithelial populations within individual tumors149,269, which represent multiple PDAC subtypes within the same tumor270.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [149]
Single-cell RNA sequencing confirmed that human and murine pancreatic tumors contain multiple CAF populations and enabled apCAF discovery.
“scRNA-seq data confirmed the existence of multiple CAF populations within human and murine pancreatic tumors and allowed the discovery of apCAFs149.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [149]
The TME comprises a large CAF population with subsets of fibroblasts of diverse phenotypes.
“In addition to immune cells, the TME comprises a large CAF population with subsets of fibroblasts of diverse phenotypes77,222–226.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [77]
Activated fibroblasts and myofibroblasts abundantly secrete various ECM proteins, and matrix metalloproteases, cathepsins and other ECM remodeling enzymes.
“Indeed, activated fibroblasts and myofibroblasts abundantly secrete various ECM proteins, and matrix metalloproteases, cathepsins and other ECM remodeling enzymes77,224,235,236.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [77]
TGF-β signaling in CAFs is increasingly seen as a determinant of resistance to immunotherapy.
“TGF-β signaling in CAFs is increasingly seen as a determinant of resistance to immunotherapy21,23,77.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [77]
Melanomas and urothelial carcinomas intrinsically resistant to anti-PD-1/PD-L1 therapy show elevated TGF-β signaling, particularly in the stromal compartment of immune-excluded tumors.
“Melanomas and urothelial carcinomas that are intrinsically resistant to anti-PD-1/PD-L1 therapy show elevated TGF-β signaling, particularly in the stromal compartment of immune excluded tumors21,77,228,361.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [77]
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- Authors
- Dominguez, C. X., Müller, S., Keerthivasan, S., Koeppen, H., Hung, J., Gierke, S., Breart, B., Foreman, O., Bainbridge, T. W., Castiglioni, A., Senbabaoglu, Y., Modrusan, Z., Liang, Y., Junttila, M. R., Klijn, C., Bourgon, R., & Turley, S. J.
- Affiliations
- Genentech (US)
- 1Department of Cancer Immunology, Genentech, South San Francisco, California.
- 2Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, California.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2020-02-01
- Volume
- 10
- Issue
- 2
- Pages
- 232-253
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2986162201
- Cited by
- 857
- References
- 73
- Citations by year
- 2026: 133 · 2025: 138 · 2024: 144 · 2023: 142 · 2022: 137 · 2021: 115 · 2020: 48
- FWCI
- 31.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Genentech
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- LRRC15, cancer-associated fibroblasts, pancreatic ductal adenocarcinoma, tumor microenvironment, myofibroblasts, TGF-beta signaling, cancer immunotherapy response, PD-L1 blockade, immune checkpoint blockade, single-cell transcriptomics, treatment response prediction
- MeSH terms
- Cancer-Associated Fibroblasts, RNA-Seq, Immune Checkpoint Inhibitors, Animals, Clinical Trials as Topic, Disease Models, Animal, Humans, Membrane Proteins, Pancreatic Neoplasms, Gene Expression Regulation, Neoplastic, Transforming Growth Factor beta, Treatment Outcome, Drug Resistance, Neoplasm, Cell Lineage, Computational Biology, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Mice, Myofibroblasts, Single-Cell Analysis, Tumor Microenvironment, B7-H1 Antigen
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