Table 3.
CAF subtypes in PDAC
| PDAC CAF Subtype | Other Nomenclature | Subtype Defining Markers (in combination with pan-CAF markers, observed across data sets) | Potential Functions | Potential Cell of Origin | Potential Targeting Agents (nonselective) |
|---|---|---|---|---|---|
| myCAF (20, 24, 64, 73, 111, 273) | •Myofibroblastic CAFs | •αSMAHigh | •ECM producing: loss of αSMA+ CAFs has been associated with ECM depletion (24, 161, 215, 221, 248, 330) | •Can originate from PSCs (24, 213, 273) | •TGFBR inhibitors, TGF-β antibodies, losartan |
| •Myofibroblasts | •CTGF | •Immunosuppressive: express TGF-β (24, 64, 73) | •Pericytes (similar transcriptional profile) | •SMO inhibitors (IPI-925, Vismodegib, LDE225) | |
| •FB3 | •TAGLN | •Tumor restraining: loss of αSMA+ CAFs has been associated with reduced survival and increased vascularization and/or recruitment of immunosuppressive cell populations (161, 221, 248) | •Col4a1+ ENG+ C4 fibroblasts (64) | ||
| •C2 | •THY1 | ||||
| •LRRC15 (subset) | |||||
| iCAF (20, 24, 64, 73, 111, 273) | •Inflammatory CAFs | •αSMALow | •Immunosuppressive: express ligands (e.g., CXCL12, CXCL1, IL6, G-CSF, …) involved in T cell exclusion and neutrophil recruitment (24, 73, 213, 273) | •Can originate from PSCs (24, 213, 273) | •JAK/STAT inhibitors |
| •FB1 | •CXCL12 | •Tumor promoting: induce phospho-STAT3 in PDAC organoids (213); loss of iCAFs leads to smaller tumors (24) | •Fbn1+ LY6C+ DPP4+ C3 fibroblasts (64) | •IL1R antagonist | |
| •C8 | •C3 | •Overlapping functions with senescent fibroblasts: iCAF secretome ~ SASP (24, 73, 213, 273) | •NF-κB inhibitors | ||
| •IL6 | |||||
| •Ly6CHigh | |||||
| •PDGFRαHigh | |||||
| apCAF (73) | •MHCII (Cd74, H2-Aa, H2-Ab) | •Immunomodulatory (do not express costimulatory molecules, may act as decoy receptor to inhibit optimal T cell response) | •Cannot originate from PSCs? | ||
| •Tumor promoting: express SAA3, SLPI | •Mesothelial cells (64, 73) | ||||
| •MHCII expression induced by IFN-γ |
Summary of actual and potential features of inflammatory cancer-associated fibroblasts (iCAFs), myofibroblastic CAFs (myCAFs), and antigen-presenting CAFs (apCAFs) in pancreatic ductal adenocarcinoma (PDAC). ECM, extracellular matrix; G-CSF, granulocyte colony stimulating factor; IFN, interferon; IL, interleukin; PDGF, platelet-derived growth factor; PSCs, pluripotent stem cells; SASP, senescence-associated secretory phenotype; αSMA, α-smooth muscle actin; SMO, Smoothened; TGF, transforming growth factor.