biomarkers-interactive-page

Tumor Mutational Burden (TMB)

Tumor mutational burden (TMB) is the number of somatic (acquired) mutations in tumor cells. Tumors with high TMB are potentially more likely to be recognized by the immune system.^1-8

Tumors with high TMB may generate more neoantigens, which may lead to an increase of tumor-infiltrating immune cells.^4,6,9,10

TMB is under investigation as a biomarker in I-O research.^4,6

References

1. Chen DS, Mellman I. Nature. 2017;541(7637):321-330.
2. Alexandrov LB et al. Nature. 2013;500(7463):415-421.
3. Sharma P, Allison JP. Science. 2015;348(6230):56-61.
4. Chabanon RM et al. Clin Cancer Res. 2016;22(17):4309-4321.
5. Kim JM Chen DS. Ann Oncol. 2016;27(8):1492-1504.
6. Giannakis M et al. Cell Rep. 2016;15(4):857-865.
7. Chalmers ZR et al. Genome Med. 2017;9(1):34.
8. Stratton MR et al. Nature. 2009;458(7239):719-724.
9. Rooney MS et al. Cell. 2015;160(1-2):48-61.
10. Brown SD et al. Genome Res. 2014;24(5):743-750.

Microsatellite Instability High/Deficient Mismatch Repair (MSI-H/dMMR)

Microsatellite instability high/deficient mismatch repair (MSI-H/dMMR) are indicators of genomic instability:

MSI: Represents a change in the number of nucleotide repeats in DNA sequences, resulting in a different number of repeats than when the DNA was inherited.¹

MMR: A DNA repair pathway which plays a key role in maintaining genomic stability.²

dMMR: Represents a loss of function in the MMR pathway.²

MSI-H: The presence of at least two unstable markers among five microsatellite markers analyzed (or ≥30% of the markers if a larger panel is used).³

Why is MSI-H/dMMR important? In MSI-H/dMMR patients with an increased number of mutations in a tumor, more neoantigens may be produced. Research is ongoing to determine how neoantigens are associated with increased T cell activation and how immune cell infiltration of tumors may be associated with response to therapy.

References

1. National Cancer Institute. Microsatellite Instability. http://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=285933 Accessed May 15, 2018.
2. Hause RJ et al. Nat Med. 2016; 22(11):1-9
3. Villar E et al. Nat Rev Clin Oncol. 2010;7(3):153-162.

Neoantigens

What are neoantigens? Neoantigens are newly formed antigens that have not been previously recognized by the immune system. Neoantigens can arise from altered tumor proteins formed as a result of tumor mutations or from viral proteins.

The increased presence of tumor-specific neoantigens may make a tumor more visible to the immune system, leading to a greater potential for T cell activation and infiltration.^1,2

Neoantigens are under investigation to understand their utility as a potential I-O biomarker.³

References

1. Rooney MS et al. Cell. 2015;160(1-2):48-61.
2. Brown SD et al. Genome Res. 2014;24(5):743-750.
3. Efremova M et al. Front Immunol. 2017;8:1679. doi:10.3389/fimmu.2017.01679.

The Biology of PD-L1

Programmed death ligand 1 (PD-L1), a ligand for the immune checkpoint receptor PD-1, is expressed on both tumor and immune cells.^1-4 To-date, PD-L1 expression is the most widely researched immune biomarker in oncology.⁴

PD-L1 is expressed on a variety of healthy cell types and tumor cells.⁴ Engagement of PD-L1 with PD-1 may result in the inactivation of T cells, which contributes to tumor evasion.^1,2,5,6

PD-L1 is under investigation to evaluate its potential as an I-O biomarker, both alone and in combination with other I-O biomarkers.

References

1. Freeman GJ et al. J Exp Med. 2000;192(7):1027-1034.
2. Latchman Y et al. Nat Immunol. 2001;2(3):261-268.
3. Gatalica Z et al. Epidemiol Biomarkers Prev. 2014;23(12):2965-2970.
4. Kerr KM et al. J Thorac Oncol. 2015;10(7):985-989.
5. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.
6. Keir ME et al. Annu Rev Immunol. 2008;26:677-704.

The Biology of PD-L2

Programmed death ligand 2 (PD-L2) is a cell surface protein that competes with PD-L1 for binding to PD-1.¹

PD-L2 interaction with PD-1 negatively regulates T cell proliferation, cytokine production and cytotoxic activity.²
PD-L2 has a higher affinity for PD-1 but is expressed at lower levels.^1,3
PD-L2 is expressed on tumor cells, antigen-presenting cells or APCs (e.g., macrophages and dendritic cells), and a variety of other immune and nonimmune cells.¹
PD-L2 expression can be measured by immunohistochemistry (IHC) using an anti-PD-L2 primary antibody.^1,4

Tumor expression of PD-L2 may contribute to tumor evasion of immune destruction by inactivating T cells.^1,2,5,6

References

1. Rozali EN et al.Clin Dev Immunol. 2016:656340
2. Ma W et al. J Hematol Oncol.2016; 9:47.
3. Youngak P et al. Biochem Biophys Res Commun. 2003; 307: 672-677.
4. Shi M et al.Am J Surg Pathol. 2014; 38(12): 1715-1723.
5. McDermott DF, Atkins MB. Cancer Med. 2013; 2(5):662-673.
6. Mellman I et al.Nature. 2011; 480:480-489.

Inflammation Gene Signatures

What are inflammation gene signatures? Inflammation gene signatures are gene expression profiles, which may indicate presence or absence of immune cells in the tumor microenvironment.^1-3

How are inflammation gene signatures evaluated? Inflammation gene signatures can be measured using methods such as microarrays, RNA-sequencing and gene expression panels.^4,5

Inflammation gene signatures vary across tumor types.^6,7 Inflammation gene signatures are under investigation as potential biomarkers of response to I-O therapy.

References

1. Walker MS et al. Int J Mol Med. 2008;21(1):13-17.
2. Linsley PS et al. PLoS One. 2015.;10(9)e0138726. doi: 10.1371/journal.pone.0138726.
3. Galon J et al. Immunity. 2013; 39(1):11-26.
4. Fumgalli D et al. BMS Genomics. 2014;15:1008.
5. Cesano A. J Immunother Cancer. 2015;3:42. doi: 10.1186/s40424-015-0088-7.
6. Gajewski TF et al. Nat Immunol. 2013;14(10):1014-1022.
7. Galon J et al. Science; 313(5795):1960-1964.

LAG-3

Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor that is expressed on the surface of both cytotoxic T cells and regulatory T cells (Tregs) and functions to control T cell response, activation and growth.^1,2 LAG-3 expression is being evaluated as a biomarker to predict response to therapy.³

In certain situations where T cells experience prolonged exposure to an antigen, such as cancer or chronic infection, the T cells become desensitized and lose their ability to activate and multiply in the presence of the antigen. The desensitized T cells will also progressively fail to produce cytokines (proteins that assist in the immune response) and kill the target cells.This process is called T cell exhaustion and is associated with an increased expression of inhibitory receptors, such as LAG-3.⁴

References

1. Huang CT et al. Immunity. 2004; 21:503-513.
2. Baixeras E et al. J Exp Med. 1992; 176:327-337.
3. Ascierto PA et al. J Clin Oncol. 2017. 35(15):9520-9520.
4. Wherry, E. J. Nature Immunol. 12, 492–499 (2011).

IDO

Indoleamine 2,3-dioxygenase-1 (IDO1) is a metabolic enzyme expressed in antigen-presenting cells (APCs).^1-3

IDO1 catabolizes tryptophan, an amino acid essential for cytotoxic T cell survival, into immunosuppressive kynurenine.^1-5 Tumor cells can upregulate IDO1 expression in order to improve the chances of their survival.⁶

Increased IDO1 expression has been associated with decreased T cell proliferation and increased Tregs in several types of cancer.^7,8

References

1. Mellor AL et al. Immunol Today. 1999;20(10):469-473.
2. Munn DH et al. J Exp Med. 1999;189(9):1363-1372.
3. Munn DH et al. Science. 2002;297(5588):1867-1870.
4. Lee GK et al. Immunology. 2002;107(4):452-460.
5. Mellor AL et al. Nat Rev Immunol. 2004;4(10):762-774.
6. Liu P et al. BMC Cancer. 2009;9:416.doi:10.1186/1471-2407-9-416.
7. Holmgaard RB et al. Cell Rep. 2015;13(2):412-424.
8. Brandacher G et al. Clin Cancer Res. 2006;12(4):1144-1151.

Tregs

Regulatory T cells (Tregs) are suppressive cells that inhibit the immune response by modulating the activation of effector T cells.¹Tregs are important in maintaining self-tolerance and preventing autoimmunity.^1,2The increased infiltration of Tregs into the tumor microenvironment has been observed in a variety of tumor types.³ The presence and activity of Tregs in tumor tissue and blood can be evaluated by cell-sorting technology such as flow cytometry.⁴

References

1. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.
2. Melero I et al. Nat Rev Cancer. 2015;15(8):457-472.
3. Nishikawa H et al. Curr Opin Immunol. 2014;27:1-7.
4. Santegoets SJ et al. Cancer Immunol Immunother. 2015;64(10):1271-1286.

MDSCs

Myeloid-derived suppressor cells (MDSCs) are recruited to the tumor microenvironment to suppress effector cell responses through mechanisms including the promotion of T cell exhaustion and dysfunction.^1,2 Increased presence of MDSCs in the tumor microenvironment has been observed in a variety of solid tumors.² The presence of MDSCs in tumor tissue and blood can be evaluated by cell-sorting technology such as flow cytometry.³

References

1. Joyce JA, Pollard JW. Nat Rev Cancer. 2009;9(4):239-252.
2. Kumar V et al. Trends Immunol. 2016;37(3):208-220.
3. Vasquez-Dunddel D et al. J Clin Invest. 2013;123(4):1580-1589.

Germline Mutations

Germline mutations are inherited and found in every cell of the host, whereas somatic mutations are acquired and found in a limited number of cells.^1,2

Germline mutations can have varied effects, including increased production of growth factors and cytokines, increased neutrophil infiltration and altered immune gene expression.^2,3-6

Germline mutations are under investigation as a biomarker of response to I-O therapy.²

References

1. National Cancer Institute. NCI Dictionary of Cancer Terms [dictionaries]. http://www.cancer.gov/publications/dictionaries/cancer-terms. Accessed September 10, 2018.
2. Sharma P et al. Science. 2015;348(6230):56-61.
3. Coulie PG et al. Nat Rev Cancer. 2014;14(2):135-146.
4. Cereda M et al. Nat Commun. 2016;7:1 2072.
5. Domagala P et al. PloS One. 2015;10(6):e0130393.
6. Bonadona V et al. JAMA. 2011(22):2304-2310.

Microbiome

The microbiome is a collection of bacteria and other organisms that actively colonize a particular environment (e.g., gut and oral cavity).^1-4 Emerging research suggests abrogation and/or alteration of the microbiota may play a role in the incidence and progression of cancer.⁵

Research into how the microbiome may be an indicator of response to I-O therapy is ongoing.

References

1. National Cancer Institute. NCI Dictionary of Cancer Terms [dictionaries]. http://www.cancer.gov/publications/dictionaries/cancer-terms. Accessed September 10, 2018
2. Turnbaugh PJ et al. Nature. 2007;449(7164):804-810.
3. Routy B et al. Science. 2018;359(6371)91-97.
4. Gopalakrishnan V et al. Science. 2018;359(6371):97-103.
5. Zitvogel L et al. Sci Transl Med. 2015;7(271):271:ps1.doi:10.1126/scitranslmed.3010473.