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Chien, Kelly S

Colla, Simona

Daher, May

Ganan-Gomez, Irene

Garcia-Manero, Guillermo, MD

Kim, Yi June

Kumar, Bijender

Ma, Feiyang

Montalban-Bravo, Guillermo

Takahashi, Koichi, MD, PhD

Wildeman, Bethany E

Yang, Hui

English

OpenWorks @ MD Anderson

• Myelodysplastic syndromes (MDS): clonal stem cell malignancies• Standard therapy not curative, transient responses, poor prognosis• Are prevention or early intervention possible in MDS? • Clonal cytopenias of undetermined significance (CCUS): aging-related premalignant state, low-grade clonal hematologic disorders at high risk of progression to MDS and leukemia • HSC-intrinsic alterations and extrinsic inflammatory factors cooperate to induce abnormal differentiation in CCUS (Ganan-Gomez et al. ASH Meeting 2021). BackgroundImmune microenvironment dysfunctions enable malignification at the onset of MDS• Characterize early alterations in the bone marrow (BM) immune microenvironment that lead to the expansion of the MDS cloneAim• BM mononuclear cells (MNCs) from patients with CCUS and young and elderly healthy donors (HDs)• Single-cell transcriptomics (scRNA-seq) • In vitro functional assays• Single-cell genomics/antigen expression analysis (Tapestri)Methods1. BM Innate Immune Cells Are Activated in CCUS PatientsB cellsB pro PCscDCsMy/MonopDCsEr HSPCsCCUS (n=4)Elderly HD (n=2)Young HD (n=2)CD8+T cellsNK cellsCD4+ T cellsCD8+T cellsNK cellsCD4+ T cellsscRNA-seq in BM MNCsCD4 TCD8 T NKFormation of ATP by chemiosmotic couplingInterferon alpha/beta signalingNeutrophil degranulationMitochondrial translation initiationCytokine Signaling in Immune systemMembrane TraffickingEukaryotic Translation ElongationRespiratory electron transport, ATP synthesis by chemiosmotic couplingAdaptive Immune SystemParasite infection0 10 20 30 40 50-Log10[P val]Pathway analysis of significantly upregulated genes in CCUSGanan-Gomez I, Ma F, Chien KS, Yang H, Montalban-Bravo G, Wildeman BE, Kumar B, Kim YJ, Daher M, Takahashi K, Garcia-Manero G and Colla S 2. Inhibitory Crosstalk Predicted Between NK and CD8+ T Cells in CCUS3. CCUS NK/T Cells Are Terminally Differentiated toward ExhaustionLigand-expressing cellsReceptor-expressing cellsNK cell activation by CD8+ T cellsHLA-E:CD94/NKG2CCD58:CD2FASLG:TNFRSF1AImmunosuppresion of CD8+ T cells by NK cellsCD48:CD244TGFB1:TGFBR1CellPhoneDB analysis of DEGsscRNA-seq in sorted CD3+ T and CD56+ NK cellsCCUS (n=3)Elderly HD (n=2)Young HD (n=2)CD4 TCD8 TNKCytoTRACE differentiation scores Exhaustion marker expressionCCUSElderlyYoungImmune microenvironment dysfunctions enable malignification at the onset of MDSGanan-Gomez I, Ma F, Chien KS, Yang H, Montalban-Bravo G, Wildeman BE, Kumar B, Kim YJ, Daher M, Takahashi K, Garcia-Manero G and Colla S T ProgCD8 + TCD4 + TNK cellsB cellscDCpDCMy/MonoCD16+ MonoDNM3TATP53• The innate immune repertoire is molecularly and functionally altered in patients with CCUS• Immune evasion of premalignant clones may contribute to clonal evolution to MDS• Rationale for adoptive NK cell therapy in patients with CCUS or low-burden MDS to prevent/arrest MDS progressionConclusions4. NK Cells from CCUS Patients Are Irreversibly Dysfunctional5. NK Cells Are Part of the Mutant CCUS Clone 0 10 20 30 40 500200400600Time (h)% Normalized K562 countsK562 aloneYoung HDsOld HDsCCUS✱✱✱✱✱✱✱✱0 3 6 9 12050100150200250Time (h)% Normalized THP1 countsYoung HealthyOld HealthyCCUSTHP1 alone✱✱✱✱✱✱Post-7-day NK cell expansionNo expansionIn vitro cytolysis assays with leukemic cell linesImmune microenvironment dysfunctions enable malignification at the onset of MDSGanan-Gomez I, Ma F, Chien KS, Yang H, Montalban-Bravo G, Wildeman BE, Kumar B, Kim YJ, Daher M, Takahashi K, Garcia-Manero G and Colla S Joint scDNA-seq and surface protein analysis (Tapestri)

Immune microenvironment dysfunctions enable malignification at the onset of myelodysplastic syndromes

https://openworks.mdanderson.org/cgi/viewcontent.cgi?article=1002&amp;context=leading-edge

Immune microenvironment dysfunctions enable malignification at the onset of myelodysplastic syndromes

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