Background
Components | Classification | Molecular characteristics | Function in TME | Major Role | |
---|---|---|---|---|---|
Immune cells | |||||
T lymphocytes | |||||
CD8+ T cell | TME & TIME | CD3+CD8+ | Cytotoxicity | Anti-tumoral | |
Th1 cell | TME & TIME | CCR6+CXCR3+ | Production of IL-2 and IFN-γ | CD8+ T cell supporting | Anti-tumoral |
Th2 cell | TME & TIME | Production of IL-4, IL-5 and IL-13 | B cell responses supporting | Pro-tumoral | |
Th17 cell | TME & TIME | Production of IL-17A, IL-17F, IL-21, IL-22 | Angiogenesis, tumorigenesis, immune regulation | Ambiguous | |
Treg cell | TME & TIME | CD4+FOXP3+CD25+ | Immune suppression | Pro-tumoral | |
B lymphocytes | TME & TIME | CD19+CD20+CD138+ | Antibody production, antigen presentation, TLSs formation | Anti-tumoral | |
Innate lymphoid cell (ILCs) | |||||
ILC1s | |||||
NK cells | TME & TIME | Expression of T-bet; Eomes+ CD27− | Cytotoxic functions without prior sensitization | Anti-tumoral | |
Non-NK cells | TME & TIME | Expression of T-bet; Eomes− CD27+ | Secretion of IFN-γ and TNF-α to induce tumor dependent anti-tumor immune responses | Ambiguous | |
ILC2s | TME & TIME | Expression of GATA3; secretion of type 2 cytokines | Secretion of IL-5, IL-13, IL-4 to inhibit anti-tumor immunity | Pro-tumoral | |
ILC3s | TME & TIME | Expression of RORγt | Heterogeneous cells secreting various cytokines and chemokines | Ambiguous | |
Tumor-associated macrophages | HLA-DR+CD68+ CD11c− | ||||
M1 | TME & TIME | CD86+ CD80+ iNOS+ | Promoting anti-tumor TH1 and TH17 immune responses | Anti-tumoral | |
M2 | TME & TIME | CD163+CD206+ | Supporting angiogenesis, tumor progression, and metastasis; immune suppression | Pro-tumoral | |
MDSCs | TME & TIME | CD11b+HLA-DR− | Differentiating into TAMs, immune suppression | Pro-tumoral | |
Dendritic cells | TME & TIME | Siglec-H+CD317+ | Binary immune regulatory function shaped by TME | Ambiguous | |
Neutrophils | CD14+HLA-DR+CD206−CD86− | ||||
N1 | TME & TIME | Supported by TGF-β and G-CSF | Immune respond initiation, antigen presenting | Anti-tumoral | |
N2 | TME & TIME | Supported by IFN-γ and hepatocyte growth factor | Remodeling ECM, promoting angiogenesis and tumor growth | Pro-tumoral | |
Stromal cells | |||||
Cancer-associated fibroblasts | TME | Cellular markers: α-SMA, FAP-α, FSP-1/S100A4, PDGFRβ | Promoting tumor cell proliferation and invasion, angiogenesis; ECM remodeling; bidirectional immune regulation | Pro-tumoral | |
Endothelia cells | TME | Cellular markers: CD31; consisting of blood vessels | Angiogenesis, tumor metastasis | Pro-tumoral | |
Pericytes | TME | Cellular markers: Calponin, CD90, DLK, NG2, PDGF-A, SMA | Promote primary tumor growth, negative regulator of metastasis, | Pro-tumoral | |
Adipocytes | TME | Cellular markers: CD34 | Secretion of hormones, metabolites, growth factors, enzymes and cytokines | Pro-tumoral | |
Mesenchymal stem cells | TME | Cellular markers: CD105, CD90, CD117, CD133 | Forming the premetastatic niche; promoting tumor initiation and progression | Pro-tumoral | |
Vessels | |||||
Blood vessel | TME | Tubular structures formed by endothelial cells (cellular markers: CD31) | Promoting metastasis and angiogenesis, | Pro-tumoral | |
Lymph vessel | TME | Tubular structures formed by lymphatic endothelial cells (cellular markers: LYVE-1, Podoplanin, PROX1, VEGFR-3) | Foster tumor metastasis, physical link between lymph nodes and tumor | Pro-tumoral | |
Extracellular matrix | |||||
Collagen, fibronectin, elastin, laminin | TME | Complex noncellular three-dimensional macromolecular network | Physical scaffold for cell, tumor cell dissemination, depot for cytokines and growth factors | Pro-tumoral | |
Matrix metalloproteases, Cathepsins | TME | Enzymes secreted and activated by malignant cells in extracellular matrix | ECM remodeling, aiding metastasis, angiogenesis and inflammation | Pro-tumoral | |
Immune molecules | |||||
Cytokines | TME & TIME | Mainly secreted by immune cells; acting in a paracrine, autocrine or endocrine manner | Promoting leukocyte growth, survival and activation; promoting tumor immunogenicity, tumor cell proliferation, angiogenesis | Ambiguous, mainly anti-tumoral | |
Chemokines | TME & TIME | Regulation of cell movement and leukocyte attractants | Promoting tumor cell migration, invasion and metastasis; promoting immune cell migration, maturation | Ambiguous, mainly anti-tumoral | |
Extracellular nonspecific chemicals | |||||
Oxygen | TME | Aerobic cellular respiration | Favor immunosuppressive phenotypes | Ambiguous | |
Amino acids | TME | Components and substrates for various critical processes in cell metabolism and physiology | Supporting physiological processes of both tumor and immune cells, immune regulation | Ambiguous | |
Glucose | TME | Major source of energy for cells | TME dependent influence of energy metabolism in both immune and tumor cells | Ambiguous | |
Lactate | TME | Products of glycolysis | Inhibiting anti-tumor immunity, decrease the pH within the TME | Pro-tumoral | |
Carbon dioxide | TME | Products of oxidative phosphorylation | Causing tumor tissue acidosis | Ambiguous | |
Fatty acids | TME | Involvement in biological progression and cell structure | Heterogeneous consequences for different cells, leading to immunosuppressive effects | Ambiguous | |
Metal ions | TME | Involvement in biological progression | Regulating tumor and immune cells | Ambiguous |
Components | Definition | Detection methods | Detecting characteristics |
---|---|---|---|
Location of immune cells | Identification and quantification of immune cells in different compartments of tumor | H&E staining, digital pathology | Morphological differences; visual distinction of tumor compartments (i.e., sTILs, iTILs) |
Probe-based in situ imaging | Cellular markers | ||
Spatial omics | Expression signature | ||
Distance between immune cells | The shortest distance between cells | Cellular-resolution imaging and analysis algorithms | The recognition and identification of cells and their surrounding cells; determination of distance between cells |
Density of immune cells in a certain area around the tumor cell | |||
Distribution of immune regulators | Compartment-based distribution | Probe-based in situ imaging and/or spatial omics | Spatial protein or mRNA expression at cellular or subcellular resolution |
Cell-specific spatial expression and co-location | |||
Spatial proximity of paired receptor and ligand | |||
Identification of specific spatial patterns | Robust spatial architecture of immune cells with specific aggregation and distribution patterns (i.e., TLSs, peri-vascular niches) | Digital pathology | Visual spatial arrangement features of cells |
Immunohistochemistry | Pattern-specific marker | ||
Probe-based in situ imaging and/or spatial omics | Pattern-specific marker at cellular or subcellular resolution |
Emerging technologies used to characterize the spatial architecture of the TIME
Category | Name | Level | Sample preparation | Labels | Visualization | Comments | Refs. |
---|---|---|---|---|---|---|---|
Non-specific technique | H&E staining | Nonspecific structure | FFPE | Hematoxylin and eosin | Visible light | Low-cost; high flux helped by deep learning: poordiscrimination of cell subtypes | |
Probe-based in situ imaging | IHC | Peptide and protein | FFPE | Antibody-reporter (usually florescent protein) | Fluorescence, insoluble pigment, etc. | Limited detectable targets simultaneously | [26] |
FISH | DNA | FFPE | Oligonucleotides-florescent reporter | Fluorescence | Limited detectable targets simultaneously | [27] | |
CODEX | Peptide and protein | Fresh-frozen | Antibody-oligonucleotides | Fluorescence | Extended detectible targets simultaneously | [28] | |
CODEX-FFPE | Peptide and protein | FFPE | Antibody-oligonucleotides | Fluorescence | Extended detectible targets simultaneously | [10] | |
seqFISH, seqFISH + , corFISH | mRNA (sub-transcriptome) | Live section | Oligonucleotides-florescent reporter | Fluorescence | > 10,000 detectible genes simultaneously; subcellular resolution ratio | ||
MIBI, MIBI-TOF | Peptide and protein | FFPE, immobilized cell suspension | Antibodies-isotypes | Secondary ion beam | Extended detectible targets simultaneously | ||
IMC | Protein, etc. | FFPE | Antibodies-high mass tag | Ion beam | Subcellular resolution ratio; probes are not necessarily needed | ||
Spatial transcriptome | Microarray-based spatial transcriptomics | Transcriptome | Live section, FFPE | Spatial transcriptome | Pathology + Computational analysis | Restricted cellular resolution | [36] |
Microarray-based spatial transcriptomics + sc-RNAseq | Transcriptome | Live section + single-cell suspension | Spatial transcriptome | Computational matching | Mapping is based on region-cluster matching by multimodal intersection analysis | [37] | |
ZipSeq | Transcriptome | Live section | Antibody/lignoceric-oligonucleotides-zipcode | Computational matching | Exquisite design in advance is required for accuracy | [38] | |
Spatial proteome | MALDI MSI | Proteome | Fresh frozen, FFPE | – | Ion imaging | Label-free; de novo investigation |