Targeting cancer-associated fibroblasts: Challenges, opportunities and future directions

Elsevier

Available online 17 June 2022, 108231

Pharmacology & TherapeuticsAbstract

Cancer-associated fibroblasts (CAFs) are a common cell in the tumour microenvironment with diverse tumour-promoting functions. Their presence in tumours is commonly associated with poor prognosis making them attractive therapeutic targets, particularly in the context of immunotherapy where CAFs have been shown to promote resistance to checkpoint blockade. Previous attempts to inhibit CAFs clinically have not been successful, however, in part due to a lack of understanding of CAF heterogeneity and function, with some fibroblast populations potentially being tumour suppressive. Recent single-cell transcriptomic studies have advanced our understanding of fibroblast phenotypes in normal tissues and cancers, allowing for a more precise characterisation of CAF subsets and providing opportunities to develop new therapies. Here we review recent advances in the field, focusing on the evolving area of therapeutic CAF targeting.

Keywords

Tumour microenvironment

Fibroblast

Myofibroblast

Cancer-associated fibroblast

Stromal targeting

Immunotherapy

Abbreviations⍺SMA

alpha Smooth Muscle Actin

apCAF

Antigen Presenting CAF

ATRA

All-trans Retinoic Acid

CAF

Cancer-Associated Fibroblast

CAR-T

Chimeric Antigen Receptor Expressing T cell

CCL

C-C Motif Chemokine Ligand

CTLA-4

Cytotoxic T-Lymphocyte Associated Protein 4

CXCL

C-X-C Motif Chemokine Ligand

CXCR

C-X-C Motif Chemokine Receptor

EMT

Epithelial-Mesenchymal Transition

FAP

Fibroblast Activation Protein

LIF

Leukaemia Inhibitory Factor

LPAR

Lysophosphatidic Acid Receptor

MDSC

Myeloid Derived Suppressor Cell

MHC

Major Histocompatibility Complex

myoCAF

Myofibroblastic CAF

PD-1

Programmed Cell Death Protein 1

PDAC

Pancreatic Ductal Adenocarcinoma

PDGF

Platelet Derived Growth Factor

PD-L1

Programmed Death Ligand 1

PSC

Pancreatic Stellate Cell

ROS

Reactive Oxygen Species

scRNA-Seq

Single-cell RNA Sequencing

SMAD

Suppressor of Mothers against Decapentaplegic

STAT

Signal Transducer and Activator of Transcription

TGF-β1

Transforming Growth Factor beta 1

TME

Tumour Microenvironment

TNF-⍺

Tumour Necrosis Factor alpha

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