Single-cell RNA sequencing reveals stromal evolution into LRRC15+ myofibroblasts as a determinant of patient response to cancer immunotherapy.

By Claudia X. Dominguez, Sören Müller, Shilpa Keerthivasan, H. Koeppen, Jeffrey Hung, S. Gierke, Béatrice Bréart, O. Foreman, Travis W. Bainbridge, A. Castiglioni and 7 more. Cancer Discovery, 2019

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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 (CAFs) programmed by transforming growth factor beta and expressing 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 PDAC patients as well as immunohistochemistry on samples from 70 patients. Furthermore, immunotherapy clinical trials comprising over 600 patients across 6 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 non-immune elements of the tumor microenvironment to boost responses of cancer patients to immune checkpoint blockade therapy.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/574d9765a0f3509e1ce6284795c85e0bb0e6170e