Table 1 |.
Therapeutic targets in the lung tumour microenvironment
| Target | Function | Genetic perturbation |
Pharmacological agent |
In vivo validation models | Refs |
|---|---|---|---|---|---|
| Cytokines and chemokines | |||||
| CCL2 | Chemokine for monocytes that increases tumour cell extravasation and angiogenesis | NA | Monoclonal antibody | Metastasis to lung: tail vein implantation; mammary fat pad implantation | 95,121,171 |
| CCL9 | Chemokine that recruits macrophages, excludes B and T cells from the tumour mass and increases angiogenesis | NA | Monoclonal antibody | NSCLC: LSL-KrasG12D;Rosa26–1ox-STOP-lox MycERT2 GEMM | 264 |
| IL-1β | Cytokine that binds to the IL-1R to promote epithelial cell proliferation and induces IL-17 in γδT cells; also the target in the trial of canakinumab | NA | Monoclonal antibody | Metastasis to lung: subcutaneous implantation NSCLC: lkkbfl/fl;LysM-Cre GEMM treated with urethane; Ccsp-rtTA (tet-O)-KrasG12D GEMM; K14-Cre; Cdhfl/fl;Trp53fl/fl GEMM |
62,99,141 |
| IL-6 | Cytokine that promotes antiinflammatory responses, proliferation, angiogenesis, EMT and drug resistance | shRNA and siRNA | Monoclonal antibody and receptor neutralizing antibody | NSCLC: Ccsp-Cre;LSL-KrasG12D GEMM with nontypeable Haemophilus influenzae strain 12 lysate exposure; subcutaneous implantation; KrasG12D; Trp53fl/fl GEMM | 274–278 |
| IL-17 A | Cytokine released from TH17 and yδT cells, resulting in neutrophilmediated CD8+T cell suppression | NA | Monoclonal antibody | Metastasis to lung: tail vein implantation; K14-Cre;Cdhfl/fl;Trp53fl/fl GEMM | 76,99 |
| IL-23 | Cytokine that induces immune suppression via exclusion of B cells, T cells and NK cells from tumours | NA | Monoclonal antibody | NSCLC: LSL-KrasG12D;Rosa26-LSL-MycERT2 GEMM | 264 |
| TGFβ1 | Cytokine that promotes EMT, inhibits antitumour immunity and promotes resistance to targeted therapies and chemotherapies | shRNA | SB431542 (TGFβR inhibitor) | NSCLC: subcutaneous implantation | 275–277,279,280 |
| TGFβ3 | Tumour-derived cytokine that induces stromal periostin and supports CSC maintenance and expansion | TGFβR2ΔTM soluble decoy receptor | NA | Metastasis to lung: MMTV-PyMT GEMM; mammary fat pad implantation | 103 |
| Other secreted factors | |||||
| HGF | Growth factor leading to c-MET signalling and responsible for resistance to EGFR tyrosine kinase inhibitors | NA | Monoclonal antibody and antagonist (NK4) | NSCLC: subcutaneous implantation | 281–283 |
| IGF2 | Enriches CSCs via IGF1R signalling | shRNA | NA | NSCLC: subcutaneous implantation | 15,17,264 |
| Periostin | Fibroblast-derived ECM protein that supports CSC maintenance and expansion | Postn−/− mice | Monoclonal antibodies | Metastasis to lung: MMTV-PyMT GEMM; mammary fat pad implantation | 103 |
| PGE2 | Promotes FOXP3 expression and Treg cell activities to suppress antitumour immunity | Ptger2−/− mice | Monoclonal antibody | NSCLC: subcutaneous implantation | 71 |
| sRAGE | Produced by lung tumours to stimulate tumour-promoting neutrophil release from bone | Recombinant protein | NA | NSCLC: KrasLSL-G12D/WT;Trp53fl/fl GEMM; tail vein implantation | 64 |
| Tenascin C | Tumour-derived ECM protein that regulates CSC fitness in the metastatic niche | shRNA | NA | Metastasis to lung: mammary fat pad implantation; tail vein implantation | 104 |
| TIMP1 | NF-κB target that increases FAK-ERK signalling through CD63 to increase tumour proliferation | shRNA | NA | NSCLC: subcutaneous implantation; LSL-KrasG12D;CA2-Cre-shp53 GEMM | 284 |
| VEGFA | Pro-angiogenic factor that also contributes to CSC phenotypes, invasion and chemoresistance | NA | Monoclonal antibody and VEGFR inhibitors | Metastasis to lung: tail vein implantation; subcutaneous implantation; subcapsular renal implantation | 108,285 |
| Versican | ECM proteoglycan stimulating MET, proliferation and metastasis; also suppresses inflammation | shRNA | NA | Metastasis to lung: tail vein implantation; MMTV-PyMT GEMM | 105,121 |
| Cytokine and chemokine receptors | |||||
| CXCR2 | Chemokine receptor on granulocytes that enables recruitment to increase metastasis | NA | Monoclonal antibody | Metastasis to lung: tail vein implantation | 170,286 |
| CXCR4 | Chemokine receptor responding to extracellular ubiquitin after injury to increase lung metastasis | NA | Monoclonal antibody (AMD3100) | Metastasis to lung: tail vein implantation with intratracheal LPS or live Escherichia coli DH5α administration; mammary fat pad implantation with intratracheal DH5a administration | 118 |
| IL-1R | Cytokine receptor that responds to IL-1β to promote epithelial cell proliferation and induces IL-17 in γδ T cells | NA | Soluble receptor antagonist (IL-1RA) | Metastasis to lung: subcutaneous implantation NSCLC: lkkbfl/fl;LysM-Cre GEMM treated with urethane; Ccsp-rtTA (tet-O)-KrasG12D GEMM; K14-Cre; Cdhfl/fl;Trp53fl/fl GEMM |
62,99 |
| IL-1R8 | Cytokine co-receptor, negative regulator of IL receptor and TLR signalling and immune checkpoint for NK cell maturation and effector function | Il1r8−/− mice | NA | Metastasis to lung: intramuscular implantation | 113 |
| Surface receptors | |||||
| CD96 | Negative regulator of NK cell function via interaction with CD155 | Cd96−/− mice | Monoclonal antibody | Metastasis to lung: tail vein implantation; mammary fat pad implantation | 111 |
| E-selectin | Inflammation-induced adhesion molecule on endothelial cells mediating tumour adhesion | NA | Monoclonal antibody | Metastasis to lung: mammary fat pad implantation with LPS treatment | 119 |
| HMMR | Hyaluronan receptor associated with inflammation, cell survival and expansion of micrometastases | shRNA | Hyaluronidase | NSCLC: intratracheal implantation with bleomycin treatment; intraarterial implantation | 25 |
| α6β4 and α6β1 integrins | Exosome adhesion molecules regulating vascular leakiness, expression of lung-specific S100 genes and SRC signalling | ITGB4 shRNA | NA | Metastasis to lung: tail vein or cardiac implantation following exosome administration via tail vein, cardiac or retroorbital injection | 287 |
| α11β1 integrin | Adhesion molecule that interacts with collagen, induces IGF2 and increases tumour growth and metastasis | Itga11−/− | NA | Metastasis to lung: subcutaneous implantation; endobronchial implantation | 16,17 |
| LGR5 | WNT signal transduction protein increasing stem cell fitness in the metastatic niche | shRNA | NA | Metastasis to lung: mammary fat pad implantation; tail vein implantation | 104 |
| PD1 | Inhibitory receptor and negative regulator of T cell function | NA | Monoclonal antibody | NSCLC: tail vein implantation | 70,80,288 |
| TIM3 | Inhibitory receptor of T cell function and adaptive resistance mechanism to PD1 and PDL1 blockade | NA | Monoclonal antibody | NSCLC: Tet-op-EgfrT790M/L858R;Cc10-rtTA GEMM; LSL-KrasG12D GEMM | 194 |
| TLR3 | Alveolar cell pattern recognition receptor that induces metastatic niche formation via production of chemokines, pro-metastatic gene expression and neutrophil recruitment | Tlr3−/− mice | NA | Metastasis to lung: subcutaneous implantation; tail vein implantation following exosome administration via tail vein injection | 97 |
| VCAM1 | Adhesion molecule resulting in pro-survival AKT signalling upon interaction with the a4 integrin subunit | shRNA | Antibody blocking the a4 integrin subunit | Metastasis to lung: mammary fat pad implantation; tail vein implantation | 102 |
| Enzymes | |||||
| ALOX5 | Neutrophil leukotriene-generating enzyme aiding metastatic colonization | Alox5−/−mice | Zileuton | Metastasis to lung: MMTV-PyMT GEMM; tail vein implantation; mammary fat pad implantation | 98 |
| Cathepsin G | Degrades TSP1, increasing inflammation and angiogenesis | Ctsg−/− mice | Sivelestat | NSCLC: tail vein implantation with or without intranasal LPS administration; subcutaneous implantation with intranasal LPS administration | 100 |
| COX2 | Promotes FOXP3 expression and Treg cell activities to suppress antitumour immunity | Cox2−/−mice | SC58236 and celecoxib | NSCLC: subcutaneous implantation; CC10 TAg GEMM | 71 |
| HDAC6 | A HDAC that promotes Treg cell recruitment and represses activation machinery on T cells and dendritic cells | NA | ACY-1215 (ricolinostat) | NSCLC: KrasLSL-G12D/WT; Trp53fl/fl GEMM; EgfrLSL-T790M/L858R GEMM | 163 |
| IDO1 | Tryptophan-catabolizing enzyme that expands myeloid-derived suppressor cells and Treg cells and impairs T cell responses | Ido1−/− mice and siRNA | Methylthiohydantoin-DL-tryptophan and 1-methyl-D-tryptophan | NSCLC: tail vein implantation; cardiac implantation; LSL-KrasG12D GEMM | 88,89 |
| LysyL oxidase, LysyL oxidase Like 2 and LysyL oxidase Like 4 | Crosslinks basement membrane collagen IV in pre-metastatic niches for myeloid cell accumulation | shRNA and Loxl2fl/fl mice | PXS-S2B | Metastasis to lung: MMTV-PyMT+/T;MMTV-Cre+/T GEMM; tail vein implantation; mammary fat pad implantation with or without intraperitoneal tumour cell-conditioned media administration | 96,289 |
| MMP14 | Processes HB-EGF, leading to EGFR signalling and tumour growth | Dominant negative MMP14 | NSC405020 | NSCLC: tail vein implantation | 24 |
| Neutrophil eLastase | Degrades TSP1, increasing inflammation and angiogenesis | Elane−/− mice | Sivelestat | NSCLC: tail vein implantation with or without intranasal LPS administration; subcutaneous implantation with intranasal LPS administration | 100 |
| RNA binding factors | |||||
| miR-105 | Exosomal miRNA targeting ZO1; disrupts endothelial monolayers and increases metastasis | Anti-miR-105 | NA | Metastasis to lung: cardiac implantation following exosome administration via tail vein injection; mammary fat pad implantation | 94 |
| miR-122 | A vesicle miRNA that suppresses glucose uptake and pyruvate kinase, increasing metastasis | Anti-miR-122 | NA | Metastasis to lung: cardiac implantation with pre-implantation and post-implantation exosome administration via tail vein injection; mammary fat pad implantation | 290 |
| miR-143 and miR-145 | Stromal miRNAs targeting CAMK1D, leading to endothelial proliferation and angiogenesis | miR-143– miR145−/− mice |
NA | NSCLC: KrasLSL-G12D/+; Trp53fl/fl GEMM; KrasLSL-G12D/+; Trp53fl/fl; Ccsp-rtTA+ GEMM; tail vein implantation; subcutaneous implantation | 30 |
| MSI1 | RNA binding protein blocking translation of the Notch inhibitor NUMB in the metastatic niche | shRNA | NA | Metastasis to lung: mammary fat pad implantation; tail vein implantation | 104 |
ALOX5, arachidonate 5-lipoxygenase; CAMK1D, calcium/calmodulin-dependent protein kinase type 1D; CCL, CC-chemokine ligand; COX2, cyclooxygenase 2; CSC, cancer stem cell; CXCR, CXC-chemokine receptor; ECM, extracellular matrix; EGFR, epithelial growth factor receptor; EMT, epithelial-to-mesenchymal transition; FAK, focal adhesion kinase; FOXP3, forkhead box P3; GEMM, genetically engineered mouse model; HB-EGF, heparin-binding EGF-like growth factor; HDAC6, histone deacetylase 6; HGF, hepatocyte growth factor; HMMR, hyaluronan-mediated motility receptor; IDO1, indoleamine 2,3-dioxygenase 1; IGF1R, insulin-like growth factor 1 receptor; IGF2, insulin-like growth factor 2; IL, interleukin; IL-1R, IL-1 receptor; LGR5, leucine-rich repeat-containing G proteincoupled receptor 5; LPS, lipopolysaccharide; MET, mesenchymal-to-epithelial transition; miRNA, microRNA; MMP14, matrix metalloproteinase 14; MMTV, mouse mammary tumour virus; MSI1, Musashi 1; NA, not applicable; NF-κB, nuclear factor-κB; NK cell, natural killer cell; NSCLC, non-small-cell lung cancer; PD1, programmed cell death protein 1; PDL1, PD1 ligand 1; PGE2, prostaglandin E2; PyMT, polyoma middle T antigen; shRNA, short hairpin RNA; siRNA, small interfering RNA; sRAGE, soluble receptor for advanced glycosylation end product; TAg, SV40 large T antigen; TGFβ, transforming growth factor-β; TGFβR, TGFβ receptor; TGFβR2ΔTM, soluble form of TGFβR2 lacking the transmembrane domain; TH17 cell, T helper 17 cell; TIM3, T cell membrane protein 3; TIMP1, tissue inhibitors of metalloproteinase 1; TLR, Toll-like receptor; Treg cell, regulatory T cell; TSP1, thrombospondin 1; VCAM1, vascular cell adhesion protein 1; VEGFA, vascular endothelial growth factor A; VEGFR, VEGF receptor; ZO1, zona occludens 1.