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Immune Suppression Markers

Cells and proteins within the tumor and its microenvironment can suppress T-cell activation, promote T-cell exhaustion, or activate regulatory T cells (Tregs).1,2 Several exploratory Immuno-Oncology (I-O) biomarkers are associated with inhibition of the antitumor immune response.

 

LAG-3

Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor expressed on activated cytotoxic
t cells
and regulatory T cells. Increased expression on cytotoxic T cells can promote T-cell exhaustion and suppress cytotoxic T-cell function. Click below to learn more about the role of LAG-3 as a potential predictive I-O biomarker.

  • LAG-3 is an immune checkpoint receptor expressed on activated cytotoxic T cells and Tregs1,2
  • Increased LAG-3 expression on cytotoxic T cells can directly promote T-cell exhaustion3,4
  • Increased expression on Tregs can also indirectly suppress cytotoxic T-cell function 1
  • This dual function of LAG-3 can promote tumor immune evasion3-5
  • In several cancers, LAG-3 and PD-1 have been shown to be co-expressed on cytotoxic T cells, which may display a greater degree of exhaustion than cytotoxic T cells expressing LAG-3 alone6,7
  • In preclinical studies, when the PD-1 pathway is blocked, LAG-3 may be upregulated to maintain tumor growth8
LAG-3 is being investigated as a potential predictive I-O biomarker.
 

Tregs

Regulatory T cells, or Tregs, suppress the immune response by modulating the activation of effector T cells. Their increased infiltration into the tumor microenvironment has been observed in a variety of tumor types. Click below to learn more about Tregs as a potential predictive I-O biomarker.

  • Tregs, or suppressor cells, suppress the immune response by modulating the activation of effector T cells1,2
  • Tregs are important in maintaining self-tolerance and preventing autoimmunity1
  • The increased infiltration of Tregs into the tumor microenvironment has been observed in a variety of tumor types3
Tregs are under investigation as a potential predictive I-O biomarker.
 

MDSCs

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells (IMCs) that may regulate immune responses during cancer, infections, chronic inflammation, and traumatic stress. They’ve been identified in numerous tumors and are recruited to the tumor microenvironment to suppress
effector cell responses.

Click below to learn more about MDSCs as a potential I-O biomarker.
  • MDSCs are immature myeloid cells (IMCs) that may regulate immune responses during cancer, infections, chronic inflammation, and traumatic stress1
  • Normally, IMCs in the bone marrow differentiate into immune cells such as macrophages1
    • During an immune response, the activation of a complex network of signaling pathways induces the development of IMCs into MDSCs1-3
  • MDSCs are recruited to the tumor microenvironment to suppress effector cell responses through the promotion of T-cell exhaustion and dysfunction3,4
  • An increased presence of MDSCs in the tumor microenvironment has been observed in a variety of solid tumors, including urothelial carcinoma, glioblastoma, pancreatic adenocarcinoma, and breast cancer3
  • In addition, lower numbers of MDSCs may be predictive of a response to immunotherapy5
MDSCs are under investigation as a potential I-O biomarker
 

IDO1

Indoleamine 2, 3-dioxygenase-1 (IDO1) is an enzyme that initiates the breakdown of tryptophan into immunosuppressive kynurenine in the tumor microenvironment. It may be expressed on various cells, including tumor cells.

Click below to learn more about IDO1 as a potential I-O biomarker.
  • IDO1 is an enzyme that initiates the breakdown of tryptophan into immunosuppressive kynurenine in the tumor microenvironment1,2
    • Tryptophan is an amino acid essential for the survival of cells, including cytotoxic
      T cells3,4
  • IDO1 may be expressed on cells, including dendritic cells, endothelial cells, stromal, and tumor cells5
  • Tumor cells can upregulate IDO1 expression and activity in order to improve their survival6,7
  • Upregulation of IDO1 has been observed in several tumor types7
  • Increased IDO1 expression has been associated with decreased T-cell proliferation, as well as increased development of immunosuppressive Tregs7,8
IDO1 is under investigation as a potential I-O biomarker.

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References–Immune suppression markers

1. Lindau D, Gielen P, Kroesen M, Wesseling P, Adema GJ. The immunosuppressive tumour network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. Immunology. 2013;138(2):105-115. 2. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, et al.
Tumor-infiltrating NY-ESO-1–specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A. 2010;107(17):7875-7880.

References–LAG-3

1. Huang C-T, Workman CJ, Flies D, et al. Role of LAG-3 in regulatory T cells. Immunity. 2004;21(4):503-513. 2. Baixeras E, Huard B, Miossec C, et al. Characterization of the lymphocyte activation gene 3–encoded protein: a new ligand for human leukocyte antigen class II antigens. J Exp Med. 1992;176(2):327-337. 3. Goding SR, Wilson KA, Xie Y, et al. Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma. J Immunol. 2013;190(9):4899-4909. 4. Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10(1):29-37. 5. Camisaschi C, Casati C, Rini F, et al. LAG-3 expression defines a subset of CD4+ CD25high Foxp3+ regulatory T cells that are expanded at tumor sites. J Immunol. 2010;184(11):6545-6551. 6. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, et al. Tumor-infiltrating NY-ESO-1–specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A. 2010;107(17):7875-7880. 7. Vilgelm AE, Johnson DB, Richmond A. Combinatorial approach to cancer immunotherapy: strength in numbers. J Leukoc Biol. 2016;100(2):275-290. 8. Huang R-Y, Francois A, McGray AJR, Miliotto A, Odunsi K. Compensatory upregulation of PD-1, LAG-3, and CTLA-4 limits the efficacy of single-agent checkpoint blockade in metastatic ovarian cancer. Oncoimmunology. 2017. doi:10.1080/2162402X.2016.1249561.  9. Bottai G, Raschioni C, Losurdo A, et al. An immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers. Breast Cancer Res. 2016. doi:10.1186/s13058-016-0783-4.

References–Regulatory T cells

1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. 2. Melero I, Berman DM, Aznar MA, Korman AJ, Pérez Gracia JL, Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15(8):457-472. 3. Nishikawa H, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Curr Opin Immunol. 2014;27:1-7. 4. Santegoets SJAM, Dijkgraaf EM, Battaglia A, et al. Monitoring regulatory T cells in clinical samples: consensus on an essential marker set and gating strategy for regulatory T cell analysis by flow cytometry. Cancer Immunol Immunother. 2015;64(10):1271-1286.

References–MDSCs

1. Gabrilovich DI, Nagaraj S. Myeloid-derived-suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162-174. 2. Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017;5(1):3-8. 3. Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The nature of myeloid-derived suppressor cells in the Tumor Microenvironment. Trends Immunol. 2016;37(3):208-220. 4. Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9(4):239-252. 5. Yuan J, Hegde PS, Clynes R, et al. Novel technologies and emerging biomarkers for personalized cancer immunotherapy. J Immunother Cancer. 2016;4:3. doi:10.1186/s40425-016-0107-3.
6. Vasquez-Dunddel D, Pan F, Zeng Q, et al. STAT3 regulates arginase-I in myeloid-derived suppressor cells from cancer patients. J Clin Invest. 2013;123(4):1580-1589.

References–IDO1

1. Mellor AL, Munn DH. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today. 1999;20(10):469-473. 2. Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med. 1999;189(9):1363-1372. 3. Lee GK, Park HJ, Macleod M, Chandler P, Munn DH, Mellor AL. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology. 2002;107(4):452-460. 4. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 2004;4(10):762-774. 5. Vigneron N, Van baren N, Van den Eynde BJ. Expression profile of the human IDO1 protein, a cancer drug target involved in tumoral immune resistance. Oncoimmunology. 2015;4(5):e1003012. 6. Liu P, Xie B-L, Cai SH, et al. Expression of indoleamine 2,3-dioxygenase in nasopharyngeal carcinoma impairs the cytolytic function of peripheral blood lymphocytes. BMC Cancer. 2009;9:416. 7. Holmgaard RB, Zamarin D, Li Y, et al. Tumor-expressed IDO recruits and activates MDSCs in a Treg-dependent manner. Cell Rep. 2015;13(2):412-424. 8. Brandacher G, Perathoner A, Ladurner R, et al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res. 2006;12(4):1144-1151. 9. Spranger S, Spaapen RM, Zha Y, et al. Up-regulation of PD-L1, IDO, and Tregs in the melanoma tumor microenvironment is driven by CD8+ T cells. Sci Transl Med. 2013. doi:10.1126/scitranslmed.3006504.