Table 1.
List of the induced or over-expressed iICP and their ligands on CAFs in different tumors.
| ICP Superfamily | Tumor Type | Type of Analysis | Type of iICP | Origin of samples | CAF subtypes | Result of Study | Ref |
|---|---|---|---|---|---|---|---|
| B7-CD28 superfamily | NSCLC | FC | PD-L1 PD-L2 |
NSCLC tumor tissues | SM1214P+
(HLA-A, -B, -C) + Thy1+ FAP+ α-SMA+ |
CAFs in human NSCLC are functionally and phenotypically heterogeneous and provide multiple complex regulatory signals that have the potential to enhance or suppress CAF function in the TME. | (72) |
| Melanoma | FC | PD-L1 PD-L2 |
lymph nodes, soft tissue, lung, brain, and chest wall | α-SMA+ | IL-1 inhibition by vemurafenib leads to PDL 1 and PDL 2 downregulation at the CAF level. | (18) | |
| HNSCC | FC | PD-L1 PD-L2 |
HNSCC tumor tissues | CD90+
FAP+ α-SMA+ |
CAFs, unlike NFs, expressed PD-L1 and PD-L2, and the expression levels of cytokine genes, including IL6, CXCL8, TNF, TGFβ1, and VEGFA, were higher in CAFs. CAFs and their supernatant are stronger than NFs in suppressing T cell proliferation, T cell apoptosis, and inducing regulatory T cells. |
(74) | |
| Melanoma and lung cancer |
FC | PD-L2 | Tumor-bearing mice | PDPN+
PDGFRα+ PDGFRβ+ FAP-α+ |
CAFs, kill CD8+T cells in an antigen-dependent manner via PD-L2 and FASL | (75) | |
| OvC | FC | B7-H3 | OvC tumor tissue |
PDGFRβ+FAP+ high | On non-immune cells, B7-H4 expression was restricted to tumor cells, whereas B7-H3 was expressed by both tumor and stromal cells. Stromal cells of the ovarian TME expressed higher levels of B7-H3 compared to tumor cells. | (76) | |
| PC | FC | PD-L1 PD-L2 |
PC tumor tissues | CD29+, CD44+, CD73+, CD90+, CD105+
ICAM-1+, HLA class I+ α-SMA+, FAP+ PDPN+ |
CAFs expressed higher levels of the PD-L1 and PD-L2 compared to primary skin fibroblasts from healthy donors. | (27) | |
| NSCLC | qRT-PCR FC IHC |
PD-L1 | NSCLC tumor tissues | α-SMA+ | In the non-metastatic NSCLC, PD-L1 expression on CAFs is reversibly regulated by IFN-γ from activated lymphocytes and suggests the induction of anti-tumor immune responses, contributing to a better prognosis after surgery. | (77) | |
| TNBC | IHC TMA Double-IF |
PD-L1 | TNBC tumor tissues | α-SMA+ | PD-L1 expression by CAF is a novel marker for a better prognosis for patients with TNBC, IHC may be suitable for immunostaining of PD-L1+ CAF. |
(78) | |
| TNF superfamily | Melanoma | FC | HVEM | Melanoma tissues | FAP+
Melan-A- gp100- |
Compared to Dermal fibroblasts, CAFs displayed increased amounts of HVEM, a known ligand of BTLA on T cells, increased l-arginase activity, and CXCL12 release. There is also an increase in the expression of TIGIT and BTLA in CD45RO+ non-naïve/memory cytotoxic T cells following exposition to CAF in comparison to Dermal fibroblast. |
(20) |
| Ig superfamily | Melanoma | FC | VISTA | Human Melanoma tissues | FAP+
Melan-A- gp100- |
Compared to Dermal fibroblasts, CAFs displayed increased amounts of VISTA, a known ligand of BTLA on T cells, increased l-arginase activity, and CXCL12 release. There is also an increase in the expression of TIGIT and BTLA in CD45RO+ non-naïve/memory cytotoxic T cells following exposition to CAF in comparison to Dermal fibroblast. |
(20) |
| NSCLC | FC | PVR HLA-E |
NSCLC tumor tissues | α-SMA+
FAP+ |
CAFs inhibit NK cell activation by reducing their proliferation rates, the cytotoxic capacity, the extent of degranulation, and the surface expression of stimulatory receptors, while concomitantly enhancing the surface expression of inhibitory receptors in NK. There was a significant increase in NKG2A expression level in the irradiated CAF group compared to the NF group. Irradiated CAFs, compared to radiation-free CAFs, have enhanced expression of iICP ligands such as PVR and HLA-E |
(19) | |
| Others | HCC | WB | IDO | HCC tumor tissues | a-SMA+
FAP+ Fn+ FSP+ VIM+ DES+ |
PGE2 and IDO, derived from CAFs, suppress the activation of NK cells and thereby create favorable conditions for tumor progression. | (79) |
| CeCa | FC IHC UPLC |
CD39/CD73 ADO |
CAFs from MSCs of normal CeCa tissues |
CD105+
CD90+ CD73+ (HLA-ABC)+ low |
Higher expression of levels of CD39 and CD73 by CeCa−MSCs compared to NCx−MSCs was associated with the ability to suppress the proliferation, activation, and functions of cytotoxic T−cells through the generation of large amounts of Ado by CeCa−MSCs. | (80) | |
| CRC | IF qRT-PCR FACS IHC |
CD73 A2B |
Tumor-bearing mice | PDGFRα+
PDGFRβ+ FAP+ Acta2+ DES+ Postn+ Thy1+ |
CAFs constitute the prominent CD73hi population in human CRCs and two CD73−murine tumor models, including a modified CRC. High CAF abundancy in CRC tissues correlates strongly with elevated CD73 activity and poor prognosis. CAF-CD73 expression is enhanced via an ADO-A2B receptor-mediated feed-forward circuit triggered by tumor cell death, which enforces the CD73 checkpoint. | (81) |
NSCLC, Non-small cell lung cancer; HNSCC, Head and neck squamous cell carcinoma; PC, pancreatic cancer; OvC, Ovarian cancer; TNBC, Triple-negative breast cancer; HCC, Hepatocellular carcinoma; CRC, Colorectal cancer; CeCa, Cervical cancer; IHC, Immunohistochemistry; IF, Immunofluorescence; FC, Flow cytometry; qRT-PCR, Quantitative real-time reverse-transcription PCR; WB, Western blot; UPLC, Ultra-performance liquid chromatography; FACS, Fluorescence-activated cell sorting; TMA, tissue microarray; PD-L1, Programmed Cell Death Ligand 1; PD-L2, Programmed cell death-ligand 2; IDO, Indoleamine 2,3 dioxygenase; HLA-E, human leukocyte antigen E; PVR, poliovirus receptor; A2B, adenosine A2B receptor; B7-H3, CD276; CD, Cluster of Differentiation; α-SMA, Smooth muscle alpha-actin; ICAM-1, Intercellular adhesion molecule-1; FAP, Fibroblast-activation protein; PDPN, Podoplanin; PDGFR, platelet-derived growth factor receptor; HLA, Human leukocyte antigen; Thy1, CD90; Fn, Fibronectin; FSP1, Fibroblast-specific protein 1 (also called S100A4); VIM, Vimentin; Acta2, αSMA; DES, Desmin; Postn, Periostin; Melan-A, melanoma antigen recognized by T cells 1 or MART-1; Gp100, Glycoprotein 100; IL, Interleukin; TGFβ, Transforming growth factor beta; IFN-γ, Interferon-gamma; CXCL, C-X-C Motif Chemokine Ligand; VEGFA, Vascular endothelial growth factor A; B7-H4, coinhibitory molecule belongs to B7 family; FASL, Fas ligand/CD95L; TNF, Tumor necrosis factor; PGE2, Prostaglandin E2; CeCa−MSCs, Cervical cancer-derived mesenchymal stromal cells; NCx−MSCs, Normal cervix mesenchymal stromal cells; NKG2A, CD159a.