On September 19, 2024, the research team led by Prof. Zemin Zhang at the Peking University Biomedical Pioneering Innovation Center (BIOPIC) and Shenzhen Bay Laboratory published a research paper titled "Cross-tissue human fibroblast atlas reveals myofibroblast subtypes with distinct roles in immune modulation" in Cancer Cell. The study established a single-cell atlas spanning 11 human tissues under healthy, fibrotic, inflammatory, and cancerous conditions, integrating 517 samples and 269,899 fibroblasts to identify 20 fibroblast subtypes. Among these, four myofibroblast subtypes with unique immune-regulatory functions were discovered, providing critical insights into tumor microenvironment remodeling and therapeutic targeting.

 

 

Fibroblasts are key structural cells that maintain tissue homeostasis, and they exhibit diverse phenotypes under pathological conditions such as fibrosis, inflammation, and cancer, influencing disease progression and therapy resistance^[1,2]. Myofibroblasts have garnered significant attention in recent years due to their critical regulatory role in the tumor microenvironment. Studies have shown that they exert prominent immunosuppressive effects in various cancers, including pancreatic, breast, and colorectal cancers^[3-5]. However, the heterogeneity of myofibroblasts, their distribution patterns across disease states, spatial localization, and interaction mechanisms with other immune cells remain to be fully elucidated.

 

The research highlights the critical role of tissue and disease contexts in shaping fibroblast phenotypes and distribution. During chronic inflammation and fibrosis, myofibroblast subtypes gradually increase and accumulate throughout cancer progression, indicating tumor-driven remodeling of fibroblast phenotypes. By regulating fibroblast signaling and metabolic pathways, these cells ultimately contribute to the formation of an immunosuppressive TME. These findings provide strong evidence for fibroblast transcriptional plasticity, supporting the dynamic transition of fibroblasts between pro-inflammatory and immunosuppressive phenotypes during disease progression^[2].

 

Compared to other myofibroblast subtypes, LRRC15⁺ myofibroblasts exhibit terminal differentiation features and may originate from two progenitor populations: PI16⁺/COL15A1⁺ progenitor-like fibroblasts and RGS5⁺ pericytes. Multiplex immunohistochemistry confirmed that LRRC15⁺ fibroblasts in tumor regions express pericyte markers (MCAM⁺ and PDGFRβ⁺), suggesting a pericyte origin. In contrast, PI16⁺ fibroblasts localize to peri-tumoral stromal regions, with specific cytokines driving their phenotypic formation. Further analysis of spatial interactions between fibroblast subtypes and immune cells revealed that PI16⁺ fibroblasts and LRRC15⁺ fibroblasts participate in distinct spatial multicellular modules (CMs) across cancer types. PI16⁺ fibroblasts interact with CX3CR1⁺ Temra cells and LYVE1⁺ macrophages, displaying anti-tumor immune features, while LRRC15⁺ fibroblasts co-localize with SPP1⁺ macrophages in tumor nests, mediating immune exclusion. Stratifying cancer patients based on the abundance of progenitor-like or terminally differentiated myofibroblasts revealed significant prognostic differences across cancer types, supporting the divergent roles of these subtypes in the TME. This discovery provides a novel framework for patient stratification and clinical therapeutic strategies.

 

Additionally, the study identified MMP1⁺ inflammatory myofibroblasts that promote immune evasion by collaborating with Treg cells and LAMP3⁺ dendritic cells to construct an immunosuppressive niche. MMP1⁺ fibroblasts recruit Tregs via pathways such as CCL2-CCR4, secrete TGF-β and IL-11 to foster immune tolerance, and release MMPs to remodel tissues, thereby influencing immune cell migration and function. Both MMP1⁺ and LRRC15⁺ fibroblast signatures are enriched in immunotherapy non-responders across multiple cancer types, highlighting their potential as combinatorial therapeutic targets in specific cancers.

 

Figure 1. Cross-Tissue Human Fibroblast Atlas

 

In summary, this study comprehensively investigates the phenotypic and distributional features of fibroblasts across diverse tissue and disease contexts, uncovering the unique roles of myofibroblast subtypes in immune regulation. These findings deepen our understanding of disease-associated fibroblasts and provide critical clues for patient stratification and the development of novel combination therapies.

 

Dr. Yang Gao (Assistant Researcher, Shenzhen Bay Laboratory), Dr. Jianan Li (Assistant Researcher, Changping Laboratory), and Wenfeng Cheng (PhD candidate, Academy for Advanced Interdisciplinary Studies, Peking University) are co-first authors of this paper. Academician Zemin Zhang (BIOPIC, Peking University) and Dr. Wenhong Hou (Guangdong Medical University Affiliated Dongguan First Hospital) are co-corresponding authors. The study was supported by Shenzhen Bay Laboratory Major Projects, Shenzhen Bay Laboratory Open Research Fund, Chinese Postdoctoral Science Foundation, and Yue-Dong Joint Fund. Computational resources were provided by the Supercomputing Center of Shenzhen Bay Laboratory.

 

Paper Link: https://www.sciencedirect.com/science/article/pii/S1535610824003192

 

References:

Biffi, G., and Tuveson, D.A. (2021). Diversity and biology of cancer-associated fibroblasts. Physiol Rev 101, 147–176.

Davidson, S., Coles, M., Thomas, T., Kollias, G., Ludewig, B., Turley, S., Brenner, M., and Buckley, C.D. (2021). Fibroblasts as immune regulators in infection, inflammation and cancer. Nat Rev Immunol 21, 704–717.

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., et al. (2022). LRRC15(+) myofibroblasts dictate the stromal setpoint to suppress tumour immunity. Nature 611, 148–154.

Foster, D.S., Januszyk, M., Delitto, D., Yost, K.E., Griffin, M., Guo, J., Guardino, N., Delitto, A.E., Chinta, M., Burcham, A.R., et al. (2022). Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin. Cancer Cell 40, 1392–1406.e1397.

Qi, J., Sun, H., Zhang, Y., Wang, Z., Xun, Z., Li, Z., Ding, X., Bao, R., Hong, L., Jia, W., et al. (2022). Single-cell and spatial analysis reveal interaction of FAP(+) fibroblasts and SPP1(+) macrophages in colorectal cancer. Nat Commun 13, 1742.