Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives

Mao, Xiaoqi; Xu, Jin; Wang, Wei; Liang, Chen; Hua, Jie; Liu, Jiang; Zhang, Bo; Meng, Qingcai; Yu, Xianjun; Shi, Si

doi:10.1186/s12943-021-01428-1

Molecular Cancer

Table 4 Diverse designed drugs that potentially target CAF-associated effector molecules, signaling pathways and matrix proteins

From: Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives

Drugs	Mechanisms	Combination therapy	therapeutic effects	Cancer models	Status	Refs
All-trans retinoic acid (ATRA)	Retinol levels restoration, PSC de-activation	None	Increases T-cell infiltration and Inhibits tumor growth and invasion	PDAC	Preclinical	[312]
Galunisertib	TGF-βR1 inhibition	Gemcitabine	Prolongs patients’ survival with minimal added toxicity	Pancreatic and hepatocellular cancer	Phase II	[313, 314]
Anti-CTLA4- TGF-βR2/Anti-PD-L1-TGF-βR2	TGF-βR2 and immune checkpoints inhibition	None	Decreases tumor-infiltrating Tregs and suppresses tumor progression	Breast cancer	Preclinical	[315]
Tocilizumab (monoclonal antibody)	IL-6-JAK/STAT3 signaling pathway inhibition	Carboplatin/Doxorubicin	Enhances antitumor immunity and provides survival benefits	Recurrent epithelial ovarian cancer	Phase I	[316]
CCX872	CCL2-CCR2 signaling axis inhibition	FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin)	Restricts immune suppression and improves clinical prognosis	Pancreatic cancer	Phase I	[317, 318]
AMD3100	CCR4 inhibition	Anti-PD-L1 therapy	Promotes T-cell accumulation and eliminates cancer cells	Pancreatic cancer	Preclinical	[114]
F16-IL-2	Tenascin-C depletion and IL-2 delivery	Paclitaxel/ Doxorubicin	Enhances antitumor immunity and inhibits tumor growth	Breast cancer	Preclinical	[319]
VS-4718 (FAK inhibitor)	FAK-targeted inhibition	Anti-PD-1 therapy	Inhibits the infiltration of immuno-suppressive cells and improves survival	Non-small-cell lung cancer, mesothelioma and pancreatic neoplasms	Phase I	[320]
anti-TNC dsRNA (ATN-RNA)	Tenascin-C mRNA-targeted interference	Surgery	Prolongs patients’ survival and restricts tumor recurrence	Brain glioblastoma multiforme	Phase I	[321]
PEGPH20	Tumor stromal hyaluronan-targeted depletion	Gemcitabine and nab-paclitaxel	Prolongs patients’ survival with less systematic side effect	PDAC	Phase III	[322]
Losartan (angiotensin inhibitor)	Profibrotic signals inhibition	None	Facilitates drugs delivery and restricts ECM remodeling	Pancreatic and breast cancer	Preclinical	[323]

Diverse strategies in CAF-targeted immunotherapies that suppress CAF activation and function and restrict ECM remodeling
CAF cancer-associated fibroblast, PSC pancreatic stellate cell, PDAC pancreatic ductal adenocarcinoma, TGF-βR1 transforming growth factor beta receptor 1, TGF-βR2 transforming growth factor beta receptor 2, CTLA-4 cytotoxic lymphocyte-associated antigen-4, PD-L1 programmed death ligand 1, IL-6 interleukin-6, JAK Janus kinase, STAT3 signal transducer and activator of transcription 3, CCX872 one of CCR2 antagonists, CCL2 C–C chemokine ligand 2, CCR2 C–C chemokine receptor 2, AMD3100 one of CXCR4 antagonists, CCR4 C–C chemokine receptor 4, IL-2 interleukin-2, FAK focal adhesion kinase, PD-1 programmed cell death protein 1, TNC tenascin-C, PEGPH20 a PEGylated human recombinant PH20 hyaluronidase, ECM extracellular matrix

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ISSN: 1476-4598

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