Session: 703. Cellular Immunotherapies: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research
Natural killer (NK) cells are innate lymphocytes that play an important role in cancer immune surveillance and have distinct advantages over T cells as candidates for immunotherapy. Myeloid blasts are inherently susceptible to NK cell-mediated killing as they express many of the ligands recognized by NK cell activating receptors. However, malignant myeloid blasts are capable of adapting and developing defense mechanisms that allow them to evade NK cell-mediated cytotoxicity. Little is known about the mechanisms of NK cell immune evasion developed by myeloid blasts. Here, we show that NK cells from patients with myeloid malignancies display a global dysfunction with severely impaired secretory function and killing capacity. Single cell RNAseq and mass cytometry experiments revealed that these NK cells from MDS and AML patients display an exhausted phenotype at the transcriptomic and proteomic levels. We also show that these NK cells have an altered metabolism compared with age matched healthy control NK cells. We show that this dysfunction is mediated by a crosstalk between myeloid blasts and NK cells and cell-cell contact dependent release of transforming growth factor beta (TGF-β). This crosstalk leads to a profound epigenetic reprogramming of NK cells driven by transcription factors known to mediate exhaustion and immune suppression. Myeloid blast-induced NK dysfunction and epigenetic state of exhaustion can be prevented by pharmacologically inhibiting the TGF-β pathway or knockout of TGFBR2 in NK cells. However, our data reveal that once this dysfunction occurs it is irreversible owing to epigenetic scarring driven by the transcription factor BATF. In fact, we show that TGF-β induces the expression of BATF in NK cells, which in turn mediates a gene regulatory program leading to NK cell dysfunction by driving the expression of exhaustion and inhibitory genes (e.g. HAVCR2, ENTPD1, CTLA4, TGFBR2).
Collectively, our findings reveal a novel mechanism of NK cell immune evasion manifested by stable epigenetic rewiring and inactivation of NK cells by myeloid blasts. Our data support the use of allogeneic sources for adoptive NK cell therapy in combination with strategies aiming at preventing immune suppression to treat myeloid malignancies rather than therapies aiming at reversing or rescuing the function of autologous NK cells.
Disclosures: Basar: Affimed: Other: R. B. and The University of Texas MD Anderson Cancer Center have an institutional financial conflict of interest with Affimed GmbH. ; Takeda: Other: R. B. and The University of Texas MD Anderson Cancer Center have an institutional financial conflict of interest with Takeda Pharmaceutical. . Uprety: Takeda: Other: N.U. and The University of Texas MD Anderson Cancer Center have an institutional financial conflict of interest with Takeda Pharmaceutical. . Li: Takeda: Patents & Royalties. Acharya: Takeda: Other: S. A. and The University of Texas MD Anderson Cancer Center have an institutional financial conflict of interest with Takeda Pharmaceutical. . Lin: Takeda: Patents & Royalties, Research Funding. Rafei: Takeda: Other: H. R. and The University of Texas MD Anderson Cancer Center have an institutional financial conflict of interest with Takeda Pharmaceutical. . Banerjee: Takeda: Patents & Royalties, Research Funding. Shaim: Takeda: Patents & Royalties. Kerbauy: Takeda: Patents & Royalties. Ang: Takeda: Patents & Royalties. Liu: Takeda: Patents & Royalties. Champlin: Cell Source: Research Funding; Kadmon: Consultancy; Johnson & Johnson/Janssen: Consultancy; Omeros: Consultancy; Actinium Pharmaceuticals: Consultancy; Arog: Consultancy; Orca Bio: Consultancy; Takeda Corporation: Patents & Royalties. Kantarjian: Precision Biosciences: Honoraria; Ascentage Pharma Group: Honoraria; Novartis (Inst): Research Funding; Pfizer: Honoraria; AstraZeneca/MedImmune: Honoraria; Abbvie: Consultancy, Honoraria; Daiichih-Sankyo (Inst): Honoraria, Research Funding; Immunogen (Inst): Honoraria, Research Funding; Astellas Pharma: Honoraria; Bristol-Myers Squibb (Inst): Research Funding; Ascentage Pharma (Inst): Research Funding; Jazz Pharmaceuticals (Inst): Honoraria, Research Funding; Abbvie (Inst): Research Funding; Taiho Pharmaceutical: Honoraria; Shenzhen Target Rx: Honoraria; Novartis: Honoraria; KAHR Medical: Honoraria; Amgen (Inst): Research Funding; Ipsen: Honoraria; Amgen: Honoraria. Marin: Affimed: Patents & Royalties; Takeda: Patents & Royalties. Abbas: Genentech: Research Funding; Illumina: Other: In-kind products ; Molecular Partners: Consultancy; Gilead: Research Funding. Shpall: Takeda: Other: License agreement; Affimed: Other: License agreement; Navan: Membership on an entity's Board of Directors or advisory committees; Fibrobiologics: Membership on an entity's Board of Directors or advisory committees; Axio: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Celaid Therapeutics: Membership on an entity's Board of Directors or advisory committees; NY Blood Center: Membership on an entity's Board of Directors or advisory committees; Syena: Other: License agreement. Rezvani: Takeda: Patents & Royalties; Affimed: Other: License agreement. Daher: Takeda: Patents & Royalties.
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