Inflammation perturbs NK cell phenotype and function in chronic myeloid leukemia (CML)

Abstract Natural killer (NK) cells have the capacity to recognize and clear cancer by releasing cytotoxic granules. In fact, NK cells’ mature phenotype abundance are associated with prolonged treatment-free remission in chronic myeloid leukemia (CML). However, cell anti-leukemic activity is suppressed during disease, environmental triggers of this impairment not fully characterized. Given role inflammatory cytokines progression malignancies, we define their impact on function a BCR-ABL1 +CML chimeric mouse model. Consistent clinical observations, reduced counts leukemic mice, display immature phenotype, low degranulation rate, altered expression activating inhibitory receptors. Single-cell RNAseq analysis confirmed these observations at transcriptional level, revealed enrichment genes pathways cytokine response (e.g., GM-CSF, LTα/β, XCL1, IL-6st, IL-2Ra, SOCS1/2/3, CIS; IL-6/STAT3 TNFa/NF-kB pathways) CML-exposed cells. To validate relevance our findings, characterized from CML patients. As expected, frequencies cohort diminished K562-targeted degranulation. Mirroring scRNAseq data, patient possess pro-inflammatory gene signature activation JAK-STAT, TNFa/NF-kB, PI3K-Akt signaling pathways. likely triggered cytokines, found that serum dampens ex vivo capacity. Thus, speculate sensitive CML-associated inflammation represents an optimal target for NK-boosting immunotherapies.