Tumor Antigens

Tumor antigens are recognized as nonself or foreign by the host immune system.¹ They can initiate the adaptive immune response, a process known as immunologic priming.^1,2 Several I-O biomarkers related to tumor antigens are currently under investigation:

Topics

Neoantigens
TMB
(MSI-H/dMMR)

Neoantigens

Neoantigens are newly formed antigens that have not been previously recognized by the immune system. They can arise from altered peptides formed as a result of tumor mutations or viral proteins.^1,2

Neoantigens can be recognized by the immune system as nonself, and as such, can elicit an immune response.^2,3 Neoantigen-specific T cells have been identified in several human cancers.⁴ High tumor mutation burden (TMB) and/or microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status may be associated with increased neoantigen production.^3,5-7

Neoantigens are under investigation as a potential I-O biomarker. As immunogenic neoantigens can be challenging to identify directly, TMB may potentially be used as a surrogate to indirectly assess neoantigen load.^8,9

Tumor mutation burden (TMB)

Tumor mutation burden (TMB) is defined as the collective number of somatic (acquired) mutations in the tumor genome.^1,2 The number of mutations can vary across different tumor types.^3,4

Tumors with high mutation burden have the potential to generate a larger number of neoantigens, making them more immunogenic.⁵ The increased presence of tumor-specific neoantigens leads to an increased number of tumor-infiltrating immune cells.⁶ High TMB has been shown to be associated with infiltration of cytotoxic T cells into the tumor microenvironment, supporting its use as a neoantigen surrogate.^7-9

Distinct mechanisms of DNA mutation, such as dMMR and exposure to environmental mutagens (eg, tobacco smoke and UV light), can lead to a higher frequency of TMB.^3,10

TMB is measured using next-generation sequencing (NGS), assessing either the whole genome, whole exome, or a comprehensive gene panel.^1,11 The threshold for defining a high level of TMB is currently under investigation, as levels of TMB can vary across tumors.^1,4

Research to investigate the potential use of TMB as an I-O biomarker is ongoing.

Microsatellite instability high/deficient mismatch repair
(MSI-H/dMMR)

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

MSI-H: Microsatellite instability (MSI) is 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 An MSI-H tumor has at least 2 unstable markers among 5 microsatellite markers analyzed (or ≥30% of the markers if a larger panel is used).²

dMMR: Mismatch repair (MMR) is a key DNA repair system. dMMR represents a loss of function in the MMR pathway.³

In MSI-H/dMMR tumors, more neoantigens may be produced.^3,4 Neoantigens have been associated with increased T-cell activation and immune-cell infiltration of the tumor microenvironment.^5,6

MSI status is most commonly detected by using polymerase chain reaction (PCR), while dMMR status is commonly detected by immunohistochemistry (IHC) for loss of expression of MMR proteins.^3,7

Research to better understand the role of MSI-H/dMMR as I-O biomarkers is ongoing.

Next Inflamed Tumor
Markers

REFERENCES: Tumor antigens

1. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69-74. 2. Eggermont LJ, Paulis LE, Tel J, Figdor CG. Towards efficient cancer immunotherapy: advances in developing artificial antigen-presenting cells. Trends Biotechnol. 2014; 32(9):456-465.

REFERENCES: Neoantigens

1. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69-74. 2. Lu Y-C, Robbins PF. Cancer immunotherapy targeting neoantigens. Semin Immunol. 2016;28(1):22-27. 3. Hause RJ, Pritchard CC, Shendure J, Salipante SJ. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med. 2016;22(11):1342-1350. 4. Bobisse S, Foukas PG, Coukos G, Harari A. Neoantigen-based cancer immunotherapy. Ann Transl Med. 2016;4(14):262. 5. Bogaert J, Prenen H. Molecular genetics of colorectal cancer. Ann Gastroenterol. 2014;27(1):9-14. 6. Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9(1):34. 7. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27(8):1492-1504. 8. Chabanon RM, Pedrero M, Lefebvre C, Marabelle A, Soria JC, Postel-Vinay S. Mutational landscape and sensitivity to immune checkpoint blockers. Clin Cancer Res. 2016;22(17):4309-4321. 9. Yuan J, Hegde PS, Clynes R, et al. Novel technologies and emerging biomarkers for personalized cancer immunotherapy. J Immunother Cancer. 2016;4:3.

REFERENCES: Tumor mutation burden

1. Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9(1):34. 2. Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009;458(7239):719-724. 3. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415-421. 4. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124-128. 5. Liontos M, Anastasiou I, Bamias A, Dimopoulos M-A. DNA damage, tumor mutational load and their impact on immune responses against cancer. Ann Transl Med. 2016;4(14):264. 6. Strickland KC, Howitt BE, Shukla SA, et al. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget. 2016;7(12):13587-13598. 7. Chabanon RM, Pedrero M, Lefebvre C, Marabelle A, Soria JC, Postel-Vinay S. Mutational landscape and sensitivity to immune checkpoint blockers. Clin Cancer Res. 2016;22(17):4309-4321. 8. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016;27(8):1492-1504. 9. Giannakis M, Mu XJ, Shukla SA, et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 2016;15(4):857-865. 10. Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214-218. 11. Ng SB, Turner EH, Robertson PD, et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature. 2009;461(7261):272-276.

REFERENCES: MSI-H/dMMR

1. National Cancer Institute. Microsatellite instability. www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=285933. Accessed September 29, 2017. 2. Vilar E, Gruber SB. Microsatellite instability in colorectal cancer—the stable evidence. Nat Rev Clin Oncol. 2010;7(3):153-162. 3. Hause RJ, Pritchard CC, Shendure J, Salipante SJ. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med. 2016;22(11):1-9. 4. Bogaert J, Prenen H. Molecular genetics of colorectal cancer. Ann Gastroenterol. 2014;27(1):9-14. 5. Giannakis M, Mu XJ, Shukla SA, et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 2016;15(4):857-865. 6. McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463-1469. 7. Richman S. Deficient mismatch repair: read all about it. Int J Oncol. 2015;47(4):1189-1202.