Table 2.
Induction of iICPs and their ligands on the cell surface in TME by CAFs.
| ICP Superfamily | Tumor Type | Type of Analysis | Type of iICPs | Origin of samples | CAF subtypes | Target cell | Immune modulators secreted by CAFs | Result of Study | Ref |
|---|---|---|---|---|---|---|---|---|---|
| B7-CD28 superfamily | HCC | FC WB |
CTLA4 | The foreskin of patients | ——— | DC | IL-6 | (91) | |
| Melanoma and lung cancer | FC | PD-1 | Tumor-bearing mice | PDPN+
PDGFRα+ PDGFRβ+ FAP-α+ |
CD8+T cells | ———– | CAFs support T cell suppression within the TME by a mechanism dependent on ICP activation. | (75) | |
| HCC | FC | PD-L1 | Human hepatitis B-related HCC tissues | α-SMA+ | Neutrophils | SDF1a IL-6 |
HCC-CAFs attract peripheral blood neutrophils through the SDF1a/CXCR4 pathway. HCC-CAF-derived IL-6 was responsible for the STAT3 activation of neutrophils. Following STAT3 activation, PDL1 is expressed at the surface of the neutrophil. Then neutrophils impaired T-cell function through the PD1/PDL1 signaling pathway. | (25) | |
| LUAD | qRT-PCR IHC |
PD-L1 | Human LUAD tumor tissues | α-SMA+ | Tumor cells | CXCL2 | CXCL2 produced by CAFs increases the potential to induce PD-L1 expression in lung adenocarcinoma cells. | (92) | |
| PC | FC | PD-1 CTLA-4 |
PC tumor tissues | CD29+, CD44+, CD73+, CD90+, CD105+
ICAM-1+, HLA class I+ α-SMA+, FAP+ PDPN+ |
T cell | COX-2 PGE2 |
CAFs promoted the expression of TIM-3, PD-1, CTLA-4, and LAG-3 in proliferating T-cells and contributed to a diminished immune function. CAFs strongly inhibited T-cell proliferation in a contact-independent fashion. |
(27) | |
| Melanoma and CRC | IHC FC qRT-PCR WB |
PD-L1 | Primary murine CAFs isolated from subcutaneous tissues |
α-SMA+ | Tumor cells | CXCL5 | LY294002, the inhibitor of PI3K, confirmed that CXCL5 derived by CAFs created an immunosuppression microenvironment by promoting PD-L1expression in tumor cells via PI3K/AKT signaling. | (93) | |
| BC | FC WB |
PD-L1 | Human BC tumor tissues | FSP1+
VIM+ α-SMA+ |
Tumor cells | CAF-derived exosomes | CAF-derived exosomes promote miR-92 expression in BC cells. miR-92 targets LATS2 and enhance the nuclear translocation of YAP1. The nuclear translocation of YAP1 leads to increased transcription and expression of PD-L1 in breast cancer cells. After treatment of BC cells by CAF-derived exosomes, cancer cells express higher PD-L1. |
(94) | |
| Melanoma | FC | BTLA | Human Melanoma tumor tissues | FAP+
Melan-A- gp100- |
T cell | Arginase | The expression of arginase in CAFs increased BTLA and TIGIT on CD8+ T cells. CAF interferes with intracellular CTL signaling via soluble mediators leading to CTL anergy. Increased expression of TIGIT and BTLA in CD45RO+ non-naïve/memory cytotoxic T cells following exposition to CAF as compared to Dermal fibroblast. |
(20) | |
| BC NSCLC |
FC | PD-1 CTLA4 |
Human BC tumor tissues | CAF-S1 (ecm-myCAF): FAP-hi α-SMA hi CD29 med-hi MCAM low ANTXR1+ SDC1+ LAMP5− CD45− EPCAM− CD31− CD235a− |
CD4+ T cells | ———— | Cluster 0/ecm-myCAF upregulates PD-1 and CTLA4 protein levels in Tregs, which, in turn, increases CAF-S1 cluster 3/TGFβ-myCAF cellular content. | (95) | |
| Lung cancer CRC BC |
RNA-Seq FC IHC |
CTLA-4 | Tumor-bearing mice | α-SMA+ | CD8+T cells | NOX4 enzyme | RNA sequencing of CD8+T cells from CAF-rich murine tumors and immuno-chemistry analysis of human tumors identified significant up-regulation of CTLA-4 in the absence of other exhaustion markers; NOX4 inhibition restored immunotherapy response in CAF-rich tumors. | (96) | |
| Ig superfamily | PC | FC | TIM-3 LAG-3 |
Human PC tumor tissues | CD29+
CD44+ CD73+ CD90+ CD105+ ICAM-1+ HLA class I α-SMA+ FAP+ PDPN+ |
T cell | COX-2 PGE2 |
CAFs strongly inhibited T-cell proliferation in a contact-independent fashion. CAFs promoted the expression of TIM-3, PD-1, CTLA-4, and LAG-3 in proliferating T-cells |
(27) |
| Melanoma | FC | TIGIT | Human Melanoma tumor tissues | FAP+
Melan-A- gp100- |
T cell | Arginase | The expression of arginase in CAFs increased BTLA and TIGIT on CD8+ T cells. CAF interferes with intracellular CTL signaling via soluble mediators leading to CTL anergy. Increased expression of TIGIT and BTLA in CD45RO+ non-naïve/memory cytotoxic T cells following exposition to CAF as compared to Dermal fibroblast. |
(20) | |
| BC NSCLC |
????? | TIGIT | Human BC tumor tissues | CAF-S1 (ecm-myCAF): FAP-hi α-SMA hi CD29 med-hi MCAM low ANTXR1+ SDC1+ LAMP5− CD45− EPCAM− CD31− CD235a− |
CD4+ T cells | ———— | Analysis of more than 19,000 single CAF-S1 fibroblasts from breast cancer identified 8 CAF-S1 clusters. Myofibroblasts from clusters 0 and 3, characterized by extracellular matrix proteins and TGFβ signaling, respectively, are indicative of primary resistance to immunotherapies. Cluster 0/ecm-myCAF upregulates PD-1 and CTLA4 protein levels in Tregs, which, in turn, increases CAF-S1 cluster 3/TGFβ-myCAF cellular content. | (95) | |
| Others | HCC | FC WB |
IDO | The foreskin of patients | ————— | DC | IL-6 | CAFs derived from HCC tumors facilitate the generation of regulatory DCs, which are characterized by low expression of costimulatory molecules, high suppressive cytokine production, and promotion of Treg expansion via IDO upregulation. STAT3 activation in DCs, as mediated by CAF-derived interleukin IL-6, is essential to IDO production from DCs |
(91) |
| NSCLC M26 |
FC | NKG2A | Human NSCLC tumor tissues | FAP-1+
a-SMA+ |
NK cells | ——— | There was a significant increase in NKG2A expression levels in NK cells exposed to the CAF and iCAF group compared to the Normal fibroblast group. | (19) |
NSCLC, Non-small cell lung cancer; PC, pancreatic cancer; HCC, Hepatocellular carcinoma; CRC, Colorectal cancer; LUAD, Lung adenocarcinoma; BC, Breast cancer; IHC, Immunohistochemistry; FC, Flow cytometry; qRT-PCR, Quantitative real-time reverse-transcription PCR; WB, Western blot; RNA-seq, RNA-sequencing; PD-L1, Programmed Cell Death Ligand 1; IDO, Indoleamine 2;3 dioxygenase; NKG2A, CD159a; 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; FSP1, Fibroblast-specific protein 1 (also called S100A4); VIM, Vimentin; Melan-A, melanoma antigen recognized by T cells 1 or MART-1; Gp100, Glycoprotein 100; IL-6, Interleukin 6; TGFβ, Transforming growth factor beta; SDF1, Stromal cell-derived factor 1; CXCL, C-X-C Motif Chemokine Ligand; COX-2, Cyclooxygenase-2; PGE2, Prostaglandin E2; NOX4, NADPH oxidase 4; CXCR, C-X-C chemokine receptor; miR-92, MicroRNA 92; LATS2, Large tumor suppressor kinase 2; YAP1, yes-associated protein 1; STAT3, Signal transducer and activator of transcription 3.