Inflamed Tumor Markers
Inflamed tumors show evidence of immune-cell infiltration and activation in the tumor microenvironment.1 Several biomarkers exist that are reflective of an inflamed tumor microenvironment:
Programmed death ligand 1 (PD-L1)
Programmed death ligand 1 (PD-L1), expressed on several cell types including tumor cells, is a ligand for the immune checkpoint receptor programmed death receptor-1 (PD-1), which is expressed on the surface of cytotoxic T cells.1-3 PD-L1 expression may be present at any point along a continuum of expression. Within a tumor sample, between 0% and 100% of cells may express PD-L1.3-5
- PD-L1 expression is determined by immunohistochemistry (IHC) and can be detected on tumor and immune cells5
- As multiple IHC assays are available, many studies have compared their analytical performance6,7
The expression of PD-L1 has implications for clinical relevance. PD-L1 expression may vary by tumor type, histology, location, and line of therapy.3,5,8,9
- Cutoff points for defining high PD-L1 expression may differ between tumor types9
Research is ongoing to better understand the role of PD-L1 as an I-O biomarker, both alone and in combination with other I-O biomarkers.
Programmed death ligand 2 (PD-L2)
Programmed death ligand 2 (PD-L2), expressed on several cell types including tumor cells, is a ligand for the immune checkpoint receptor PD-1, which is expressed on the surface of cytotoxic T cells.1,2 PD-L2 has a higher affinity than PD-L1 for PD-1, but is expressed at lower levels.3,4 PD-L2 may present at any point along a continuum of expression. Within a tumor sample, PD-L2 expression can range from absent to greater than 70%.3,5,6 Expression of PD-L2 may vary by tumor type, histology, and cell type.5,7-9
PD-L2 expression can be determined by IHC assay and detected on tumor and immune cells.3,9
PD-L2 is currently under investigation as an I-O biomarker.
Tumor-infiltrating lymphocytes (TILs)
Tumor-infiltrating lymphocytes (TILs) are immune cells that enter the tumor and its microenvironment to mediate an antitumor immune response. TILs include cytotoxic T cells and natural killer (NK) cells.1 Expression of key secreted factors in the tumor microenvironment, such as chemokines and proinflammatory cytokines, can recruit these immune cells to the tumor.2
Tumors can be characterized by the extent of immune-cell infiltration. The level of TILs correlates with the degree of inflammation.3,4
The number, type, and activation state of TILs found within a tumor can be identified using techniques such as IHC and cell-sorting technology such as flow cytometry.5
TILs are currently under investigation as an I-O biomarker.
Inflammation gene signatures
Inflammation gene signatures are a specific type of gene expression profile. Gene expression profiling measures the expression of mRNA across thousands of genes.1 This can create a distinct molecular profile (or gene signature), providing a holistic view of cellular function.1,2
Reflecting the combined expression of various inflammation-specific genes, inflammation gene signatures may indicate the presence or absence of immune cells in the tumor microenvironment.2 These gene signatures can contain information on the type, amount, functional orientation, and/or location of immune cells.3
Inflammation gene signatures vary across tumor types and may be a powerful diagnostic tool.4,5 The interferon gamma (IFN-γ) gene plays a major role in the activation of the immune response.6 Consisting of IFN-γ expression along with other predefined genes, the IFN-γ signature can be used to assess the level of inflammation within the tumor microenvironment.7
To assess gene signatures, mRNA is used as an intermediary to determine the expression levels of multiple genes. Techniques include targeted mRNA expression profiling, microarrays, RNA-seq, and gene expression panels (see hypothetical example of gene expression profile below).8,9
Inflammation gene signatures are being investigated as a potential I-O biomarker.
REFERENCE: Inflamed Tumor Markers
1. Masucci GV, Cesano A, Hawtin R, et al. Validation of biomarkers to predict response to immunotherapy in cancer: Volume I - pre-analytical and analytical validation. J Immunother Cancer. 2016;4:76.
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REFERENCES: Inflammation gene signatures
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