Immune Suppression Markers
Cells and proteins within the tumor and its microenvironment can suppress T-cell activation, promote
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
- 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
- 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-expressedon 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
The expression of LAG-3 can be determined using immunohistochemistry (IHC)9
LAG-3: Investigation as an I-O biomarker
See the role LAG-3 plays as a potential predictive I-O biomarkerWatch video
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
- The presence and activity of Tregs in tumor tissue and blood can be evaluated using IHC and flow cytometry4
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.
- 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
- The presence of MDSCs in tumor tissue and blood can be evaluated by cell-sorting technology such as flow cytometry6
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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.
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.
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.