Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials

Zhang, Hao; Yue, Xinghai; Chen, Zhe; Liu, Chao; Wu, Wantao; Zhang, Nan; Liu, Zaoqu; Yang, Liping; Jiang, Qing; Cheng, Quan; Luo, Peng; Liu, Guodong

doi:10.1186/s12943-023-01860-5

Molecular Cancer

Table 2 CAF Phenotypes across various cancers

From: Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials

Tumor type	Sample type	CAF Phenotype		Biomarker(s)	Ref
Pancreatic ductal adenocarcinoma	Patient, KPC mouse	myCAF		α-SMA^High, FAP	[81, 92]
		iCAF		IL-6, IL11, α-SMA^Low, PDGFRα^High
		apCAF		MHCII, CD74
Breast cancer and ovarian cancer	Patient	CAF-S1		CD29^Med FAP^High FSP1^Low−High α-SMA^High PDGFRb^Med−High CAV1^Low	[93, 94]
		CAF-S2		CD29^Low FAP^Neg FSP1^Neg−Low α-SMA^Neg PDGFRb^Neg CAV1^Neg
		CAF-S3		CD29^Med FAP^Neg FSP1^Med−High α-SMA^Neg−Low PDGFRb^Med CAV1^Neg−Low
		CAF-S4		CD29^High FAP^Neg FSP1^Low−Med α-SMA^High PDGFRb^Low−Med CAV1^Neg−Low
Breast cancer	Patient	cluster 0 (ECM-myCAF)		LRRC15, GBJ2	[93]
		cluster 1 (detox-iCAF)		ADH1B, GPX3
		cluster 2 (IL-iCAF)		RGMA, SCARA5
		cluster 3 (TGFβ-myCAF)		CST1, TGFb1
		cluster 4 (wound-myCAF)		SEMA3C, SFRP4
		cluster 5 (IFNg-i CAF)		CCL19, CCL5
		cluster 6 (IFNab-myCAF)		IFIT3, IRF7
		cluster 7 (acto-myCAF)		GGH, PLP2
Breast cancer	Patient	CAF +		ADAMTS12^High, AEBP1^High, COL10A1^High, COL11A1^High, EDNRA^High, EPPK1^High, WNT7B ^High, CXCL11^Low, CXCR6^Low	[82]
Breast cancer	Patient	CAF-		ADAMTS12^Low, AEBP1^Low, COL10A1 ^Low, COL11A1^Low, EDNRA^Low, EPPK1^Low, WNT7B ^Low CXCL11 ^High, CXCR6^High	[82]
Breast cancer	Murine	vCAF		FAP, S100a4, ACTA2, PDGFRβ	[83]
		mCAF		FAP, S100a4, ACTA2, PDGFRα
		cCAF		FAP, S100a4, ACTA2, PDGFRβ
		dCAF		FAP, Sox9, Sox10, PDGFRβ
Solid tumors	Murine and human	SSL CAF	Cluster 1	Pi16, Dpp4, Dpt, CD34	[86]
		SSL CAF	Cluster 3	Pi16, Dpp4
		MR CAF	Cluster 2	FAK
			Cluster 4	Lrrc15, Spp1
			Cluster 5	Thbs 2, FSP 1, Col 6a 1, Cdh 11
		IM CAF	Cluster 0	IL 1, IFNg, CXCL12
Gastric cancer	Patient	iCAF		IL6, CXCL12	[96]
Gastric cancer	Patient	eCAF		MMP14, LOXL2, POSTN	[96]
Colorectal cancer	Human	CAF-A		FAP, MMP2, DCN	[84, 85]
Colorectal cancer	Human	CAF-B		α-SMA, PDGFA, TAGLN	[84, 85]
Lung cancer	Patient	subtype I		HGF^High FGF7^High/Low p-SMAD2^Low	[87]
		subtype II		HGF^Low FGF7^High p-SMAD2^Low
		subtype III		HGF^Low FGF7^Low p-SMAD2^High
Lung cancer	Patient	Cluster1		COL10A1	[88]
		Cluster2		COX4I2
		Cluster3		–
		Cluster4		PLA2G2A
		Cluster5		MMP3
		Cluster6		FIGF
		Cluster7		–
Metastatic lymph nodes	Patient	CAF-S1		FAP^High CD29^Med−High αSMA^High PDPN^High PDGFRβ^High;	[89]
		CAF-S2		FAP^Neg CD29^Low αSMA^Neg−Low PDPN^Low PDGFRβ^Low
		CAF-S3		FAP^Neg−Low CD29^Med αSMA^Neg−Low PDPN^Low PDGFRβ^Low−Med
		CAF-S4		FAP^Low−Med CD29^High αSMA^High PDPN^Low PDGFRβ^Med
Ovarian cancer	Patient	CAF_c1		CCDC80, SFRP2, VCAN, COL8A1	[90]
Ovarian cancer	Patient	CAF_c2		RGS5, NOTCH3, NDUFA4L2	[90]
Melanoma, head and neck squamous cell carcinoma, and lung cancer	Patient	Pan-CAF 1(pan-myCAFs)		ACTA2, MYH11, MCAM, TAGLN	[91]
		Pan-CAF 2(pan-dCAFs)		COL1A1, COL3A1
		Pan-CAF 3(pan-iCAFs)		CFD, CXCL14, CXCL12
		Pan-CAF 4(pan-iCAFs-2)		CXCL2
		Pan-CAF 5(pan-nCAF)		CXCR4, NCAM1
		Pan-CAF 6(LQ-CAF)		C10orf10
		Pan-CAF 7(pan-pCAF)		BIRC5, TOP2A

Abbreviations: ACTA2 Actin alpha 2, ADAMTS12 ADAM metallopeptidase with thrombospondin type 1 motif 12, ADH1B Alcohol dehydrogenase 1, AEBP1 Adipocyte enhancer-binding protein 1, BIRC5 Baculoviral IAP repeat containing 5, CAV Caveolin, CCDC80 Coiled-coil domain-containing protein 80, CCL CC motif chemokine ligand, CD Clusters of differentiation, Cdh 11 Cadherin 11, CFD Complement factor D, COL1 Collagen type I, COL10A1 Collagen type X alpha 1 chain, COX4I2 Cytochrome C oxidase subunit 4I2, CST1 Cystatin, CXCL11 C–X–C motif chemokine ligand 11, CXCR6 C-X-C motif chemokine receptor 6, C10orf10 Chromosome 10 open reading frame 10, DCN Decorin, Dpp4 Dipeptidyl peptidase 4, Dpt Dermatopontin, EDNRA Endothelin receptor type A, EPPK1 Epiplakin 1, FAK Focal adhesion kinase, FGF7 Fibroblast growth factor 7, FIGF Vascular endothelial growth factor D, VEGF-D, FSP 1 Ferroptosis suppressor protein 1, GBJ2 Gap junction protein beta 2, GGH G-glutamyl hydrolase, GPX3 Glutathione peroxidase 3, IFIT3 Interferon induced protein with tetratricopeptide repeats 3, IFNg Interferon gamma, IL Interleukin, IRF7 Interferon regulatory factor 7, LRRC 15 Leucine rich repeat containing 15, Med Medium, MCAM Melanoma cell adhesion molecule, MHCII Major histocompatibility complex class II, MMP Matrix metalloproteinase, MYH1 Myosin heavy chain 1, NCAM1 Neural cell adhesion molecule 1, NDUFA4L2 NDUFA4 mitochondrial complex associated like 2, Neg Negative, NOTCH3 Neurogenic locus notch homolog protein 3, PDGFR Platelet-derived growth factor receptor, PDPN Podoplanin, Pi16 peptidase inhibitor 16, PLA2G2A Phospholipase A2 group IIA, PLP2 Proteolipid protein 2, RGMA Repulsive guidance molecule BMP co-receptor, RGS5 Regulator of G protein signaling 5, SCARA5 Scavenger receptor class A member 5, SEMA3C Semaphorin 3C, SFRP2 Secreted frizzled-related protein 2, Sox SRY-related HMG-box, Spp1 Secreted phosphoprotein 1, TAGLN Transgelin, Thbs 2 Thrombospondin 2, TOP2A DNA topoisomerase II alpha, VCAN Versican, WNT7B Wnt family member 7B, α-SMA Alpha-smooth muscle actin

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