Immune dysfunction has emerged as a key driver of HR-MDS and AML1-3

Immune dysfunction has emerged as a key driver of HR-MDS and AML

Immune dysfunction has emerged as a key driver of HR-MDS and AML1-3

Immune dysfunction has emerged as a key driver of HR-MDS and AML

Watch Dr Steensma outline how the immune system works differently in HR-MDS

  • TIM-3 may play a role in the innate and adaptive immune dysfunction of HR-MDS and AML4-8
  • This immune dysfunction allows LSCs and blasts to evade immune detection and over-proliferate4-8
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David Steensma, MD, Global Hematology Head,
Transitional Clinical Oncology, Novartis Institute for Biomedical Research, United States


Immune dysfunction inhibits the ability of immune cells to kill malignant myeloid cells, such as LSCs and blasts1-3

Increase in immune
suppressive cells

(Tregs, M2 macrophages)9,12
Decrease in
cytotoxic cells

(T cells, NK cells) and DC1-3
Cytotoxic cells
cannot kill malignant
myeloid cells

(LSCs, leukemic blasts)1
  • Immune dysfunction causes macrophages to increase anti-inflammatory signaling and leaves T cells, NK cells, and dendritic cells unable to kill malignant myeloid cells such as LSCs and blasts2,3,9
  • Leukemic stem cells and blasts are then able to multiply and spread throughout the bone marrow4,5
  • This immune dysfunction is complicated by the fact that patients are often older with already suppressed immune systems10,11


TIM-3 expression may be a key driver of immune dysfunction7,8

  • TIM-3 is expressed on LSCs, blasts, and dysfunctional immune cells involved in innate and adaptive immunity7,8
  • TIM-3 expression levels increase from low-risk MDS to high-risk MDS to AML13
  • This suggests an important role for TIM-3 in immune dysfunction associated with these diseases7,8,13


Immune dysfunction remains unaddressed in HR-MDS and AML, and current treatments continue to fall short in closing the durability gap14,15

  • Currently available treatments for HR-MDS and AML only target LSCs, and durable responses remain elusive14,15
  • Research into immune targets, such as TIM-3, is underway



Interested in risk stratification for HR-MDS and AML? Learn more from Dr Borate

Uma Borate, MBBS, Hematology Specialist and Associate Professor,
The Ohio State University Comprehensive Cancer Center James, United States

AML, acute myeloid leukemia; DC, dendritic cell; HR-MDS, higher-risk myelodysplastic syndromes; LSCs, leukemic stem cells; NK, natural killer; TIM-3, T cell immunoglobulin and mucin domain-3; Treg, regulatory T cell.

References: 1. Lopes MR, Traina F, Campos PdM, et al. IL10 inversely correlates with the percentage of CD8+ cells in MDS patients. Leuk Res. 2013;37:541-546. 2. Ma L, Ceuppens J, Kasran A, et al. Immature and mature monocyte-derived dendritic cells in myelodysplastic syndromes of subtypes refractory anemia or refractory anemia with ringed sideroblasts display an altered cytokine profile. Leuk Res. 2007;31(10):1373-1382. 3. Kiladjian J-J, Bourgeois E, Lobe I, et al. Cytolytic function and survival of natural killer cells are severely altered in myelodysplastic syndromes. Leukemia. 2006;20:463-470. 4. Chen J, Kao Y-R, Sun D, et al. Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level. Nat Med. 2019;25(1):103-110. 5. Goardon N, Marchi E, Atzberger A, et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukaemia. Cancer Cell. 2011;19:138-152. 6. Paczulla AM, Rothfelder K, Raffel S, et al. Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature. 2019;572:254-259. 7. Monney L, Sabatos CA, Gaglia JL, et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002;415:536-541. 8. 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. 9. 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;4(2):274-286. 10. National Cancer Institute. SEER Cancer Statistics Review (CSR) 1975-2016. Accessed September 29, 2020. 11. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454-2465. 12. Kordasti SY, Ingram W, Hayden J, et al. CD4+ CD25high Foxp3+ regulatory T cells in myelodysplastic syndrome (MDS). Blood. 2007;110(3):847-850. 13. Asayama T, Tamura H, Ishibashi M, et al. Functional expression of Tim-3 on blasts and clinical impact of its ligand galectin-9 in myelodysplastic syndromes. Oncotarget. 2017;8(51):88904-88917. 14. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223-232. 15. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. New Engl J Med. 2020;383(7):617-629.