Cancer-associated fibroblasts and their influence on tumor immunity and immunotherapy

  1. Richard Lee Barrett
  2. Ellen Puré  Is a corresponding author
  1. University of Pennsylvania, United States
2 figures and 1 table


Signaling Between CAFs and Immune Cells.

Red Box: Tumor cells drive activation of fibroblasts via multiple mechanisms. Fibroblasts are heterogeneously activated into different sub-populations based on the biochemical and biomechanical cues in their immediate environment. Blue Box. Key signaling pathways involved in CAF-immune cell signaling. B7H3 (CD276); 5′-nucleotidase (CD73); Chitinase 3-like 1 (Chi3L1); chemokine (C-C motif) ligand 2 (CCL2; chemokine (C-X-C motif) ligand 1 (CXCL1)); chemokine (C-X-C motif) ligand 12 (CXCL12), chemokine (C-X-C motif) ligand 16 (CXCL16), Dipeptidyl peptidase 4 (DPP4); Junctional adhesion molecule B (JAM2); Interleukin 6 (IL-6); Interleukin 8 (IL-8); Interleukin 11 (IL-11); Leukemia Inhibitory Factor (LIF), tumor necrosis factor receptor superfamily member four ligand (OX40L); Programmed cell death protein 1 (PD-1), Programmed cell death protein 2 (PD-2), Prostaglandin E2 (PGE2), Transforming growth factor beta (TGF-β), Polio Virus Receptor (PVR), CAF) (Figure created with

Therapeutic approaches to targeting of CAFs.

(1) Inhibitors of pathways known to drive fibroblast activation can block tumor cells ability to manipulate fibroblasts for their own survival. (2) The functional heterogeneity between CAF populations in the TME means that targeting specific subpopulations can be an effective strategy. Targeted therapeutics such as chimeric antigen receptor (CAR) expressing T cells (CAR-T) and antibody-drug conjugates (ADCs) can target the fibroblast sub-populations responsible for tumor protection and immunosuppression while leaving quiescent and tumor restraining populations intact. (3) Blocking CAFs ability to exert immunosuppressive/tumor promoting influence within the TME may alleviate immunosuppression and allow immunotherapies to be effective within this space. Some targets, such as TGF-β, can act both upstream and downstream, blocking CAF formation and attenuating downstream signaling in CAFs that are already established. (Figure created with


Table 1
Common markers recently used to study CAF populations that influence tumor immunity and progression.

Many potential markers have been described throughout the literature; however, this table has been limited to the markers most relevant to the topics outlined in this review.

Phenotypic markerFeatures of expressing populationsReported tumor typesSubcellular localizationRefs
Context dependent tumor promotion and/or tumor restraint
Preferentially located tumor adjacent
MostCytoplasmicÖzdemir et al., 2015; Costa et al., 2018; Zhou et al., 2018; Kato et al., 2018
Tumor promoting through immune-dependent and immune-independent mechanisms
Major producers of immunosuppressive cytokines like CXCL12 and CCL2 in the TME
MostMembraneFeig et al., 2013; Yang et al., 2016; Lo et al., 2015; Lee et al., 2011
FSP1 (S100A4)Commonly used fibroblast marker
Marks both quiescent and activated fibroblasts
Also present on macrophages
MostCytoplasmic, NuclearStrutz et al., 1995; Österreicher et al., 2011
Fibroblast sub-population that closely associates with vasculature and ducts in pancreas
Preferentially expands over other fibroblast populations during pancreatic tumor progression
PancreaticCytoplasmic, NuclearGarcia et al., 2020
Hoxb6 (HOXB6)Fibroblast sub-population present dispersed throughout healthy pancreas
Minimal contribution to desmoplasia in pancreatic tumor progression
PancreaticNuclearGarcia et al., 2020
LRRC15 (LRRC15)TGF-β-driven gene expression signature
Correlate with poor tumor immunity
PancreaticMembraneDominguez et al., 2020
Defines iCAF population in mouse, in combination with other CAF markers
Common on myeloid cells
PancreaticMembraneElyada et al., 2019; Biffi et al., 2019
Meflin (ISLR)Suppress PDAC progression
Expression correlates with CD8+ T cells, macrophages and dendritic cells in gastric cancer
Pancreatic, gastricGPI-linked
Membrane Protein
Maeda et al., 2016; Mizutani et al., 2019; Li et al., 2020
PDGFRα (PDGFRA)Pan-fibroblast marker
Marks both quiescent fibroblasts and CAFs
MostMembraneFarahani and Xaymardan, 2015; Nurmik et al., 2020
PDPN (PDPN)Associated with poor tumor immunity
Marker of follicular RCs and some macrophages
MostMembraneKitano, 2010; Astarita et al., 2012; Shindo et al., 2013; Kerrigan et al., 2012

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  1. Richard Lee Barrett
  2. Ellen Puré
Cancer-associated fibroblasts and their influence on tumor immunity and immunotherapy
eLife 9:e57243.