HR-MDS and AML are complex diseases characterized by immune dysfunction and leukemic stem cell and blast over-proliferation1-3

About myeloid diseases like HR-MDS and AML

Higher-risk MDS (HR-MDS) and acute myeloid leukemia (AML) occur when hematopoietic stem cells, or progenitor cells, transform into leukemic stem cells (LSCs), which generate blasts that fully multiply and spread throughout the bone marrow.4

Patients with these diseases are generally older and have suppressed immune systems, which may contribute to tumor immune escape.5-7

Immune system dysfunction, a hallmark of cancer, creates a suppressive immune environment in HR-MDS and AML1

Immune dysfunction affects multiple immune cells and enables leukemic stem cells (LSC) over-proliferation. Increase in immune suppressive cells, Decrease in cytotoxic cells, and Cytotoxic cells cannot kill malignant myeloid cells. The weakened immune system allows LSCs to over-proliferate and evade immune detection.

 

 

TIM-3 is expressed on LSCs, blasts (not healthy hematopoietic stem cells), and immune cells, suggesting it may play an important role in this complex disease pathophysiology9,10

TIM-3, T cell immunoglobulin and mucin domain-3.

 

 
References: 1. Wang C, Yang Y, Gao S, et al. Immune dysregulation in myelodysplastic syndrome: Clinical features, pathogenesis and therapeutic strategies. Crit Rev Oncol Hematol. 2018;122:123-132. 2. Chen J, Kao YR, Sun D, et al.  Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level. Nat Med. 2019;25(1):103-110. 3. Khaldoyanidi S, Nagorsen D, Stein A, et al. Immune biology of acute myeloid leukemia: implications for immunotherapy. J Clin Oncol. 2021; 39(5): 419-433. 4. Lane SW, Gilliland DG. Leukemia stem cells. Semin Cancer Biol. 2010;20(2):71-76. 5. National Cancer Institute. SEER Cancer Statistics Review (CSR) 1975-2016. https://seer.cancer.gov/csr/1975_2016/. Accessed April 27, 2020. 6. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454-2465. 7. Klepin HD. Myelodysplastic syndromes and acute myeloid leukemia in the elderly. Clin Geriatr Med. 2016;32(1):155-173. 8. Brück O, Dufva O, Hohtari H, et al. Immune profiles in acute myeloid leukemia bone marrow associate with patient age, T-cell receptor clonality, and survival. Blood Adv. 2020;28(4):274-286. 9. Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: Co-inhibitory receptors with specialized functions in immune regulation. Immunity. 2016;44(5):989-1004. 10. Kikushige Y, Shima T, Takayanagi S-I, et al. TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell. 2010;7(6):708-717.

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