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The surface receptor CD8[alpha] is present on 20%-80% of human (but not mouse) NK cells, yet its function on NK cells remains poorly understood. CD8[alpha] expression on donor NK cells was associated with a lack of therapeutic responses in patients with leukemia in prior studies, thus, we hypothesized that CD8[alpha] may affect critical NK cell functions. Here, we discovered that CD8[[alpha].sup.-] NK cells had improved control of leukemia in xenograft models compared with CD8[[alpha].sup.+] NK cells, likely due to an enhanced capacity for proliferation. Unexpectedly, we found that CD8[alpha] expression was induced on approximately 30% of previously CD8[[alpha].sup.- ] NK cells following IL-15 stimulation. These induced CD8[[alpha].sup.+] (iCD8[[alpha].sup.+]) NK cells had the greatest proliferation, responses to IL-15 signaling, and metabolic activity compared with those that sustained existing CD8[alpha] expression (sustained CD8[[alpha].sup.+]) or those that remained CD8[[alpha].sup.-] (persistent CD8[alpha]). These iCD8[[alpha].sup.+] cells originated from an IL- 15R[[beta].sup.hi] NK cell population, with CD8[alpha] expression dependent on the transcription factor RUNX3. Moreover, CD8A CRISPR/Cas9 deletion resulted in enhanced responses through the activating receptor NKp30, possibly by modulating KIR inhibitory function. Thus, CD8[alpha] status identified human NK cell capacity for IL-15-induced proliferation and metabolism in a time-dependent fashion, and its presence had a suppressive effect on NK cell-activating receptors., Introduction NK cells are innate lymphoid cells that protect the host from infection and malignant transformation through direct cytotoxicity and communication via cytokine and chemokine production (1-3). Human NK cells [...]

Natural killer (NK) cells are innate lymphoid cells that protect a host from viral infections and malignancies. MicroRNA‐146a (miR‐146a) is an important regulator of immune function that is highly expressed in NK cells and is further upregulated during murine cytomegalovirus (MCMV) infection. Here we utilized mice with a global targeted deletion of miR‐146a to understand its impact on the innate immune responses to MCMV infection. MiR‐146a−/− mice were protected from lethal MCMV infection, which was intrinsic to the hematopoietic compartment based on bone marrow chimera experiments. NK cell depletion abrogated this protection, implicating NK cells as critical for the miR‐146a−/− protection from MCMV. Surprisingly, NK cells from miR‐146a‐deficient mice were largely similar to control NK cells with respect to development, maturation, trafficking, and effector functions. However, miR‐146a−/− mice had increased NK cell numbers and frequency of the most mature Stage IV (CD27−CD11b+) NK cells in the liver at baseline, enhanced STAT1 phosphorylation, and increased selective expansion of Ly49H+ NK cells and T cells during MCMV infection. This study demonstrates a critical role for miR‐146a in the host response to MCMV, arising from mechanisms that include increased NK cell numbers and early T‐cell expansion. [ABSTRACT FROM AUTHOR]

Metastatic (m) colorectal cancer (CRC) is an incurable disease with a poor prognosis and thus remains an unmet clinical need. Immune checkpoint blockade (ICB)-based immunotherapy is effective for mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRC patients, but it does not benefit the majority of mCRC patients. NK cells are innate lymphoid cells with potent effector responses against a variety of tumor cells but are frequently dysfunctional in cancer patients. Memory-like (ML) NK cells differentiated after IL-12/IL-15/IL-18 activation overcome many challenges to effective NK cell anti-tumor responses, exhibiting enhanced recognition, function, and in vivo persistence. We hypothesized that ML differentiation enhances the NK cell responses to CRC. Compared to conventional (c) NK cells, ML NK cells displayed increased IFN-γ production against both CRC cell lines and primary patient-derived CRC spheroids. ML NK cells also exhibited improved killing of CRC target cells in vitro in short-term and sustained cytotoxicity assays, as well as in vivo in NSG mice. Mechanistically, enhanced ML NK cell responses were dependent on the activating receptor NKG2D as its blockade significantly decreased ML NK cell functions. Compared to cNK cells, ML NK cells exhibited greater antibody-dependent cytotoxicity when targeted against CRC by cetuximab. ML NK cells from healthy donors and mCRC patients exhibited increased anti-CRC responses. Collectively, our findings demonstrate that ML NK cells exhibit enhanced responses against CRC targets, warranting further investigation in clinical trials for mCRC patients, including those who have failed ICB. [ABSTRACT FROM AUTHOR]

Activation of natural killer (NK) cells with the cytokines interleukin-12 (IL-12), IL-15, and IL-18 induces their differentiation into memory-like (ML) NK cells; however, the underlying epigenetic and transcriptional mechanisms are unclear. By combining ATAC-seq, CITE-seq, and functional analyses, we discovered that IL-12/15/18 activation results in two main human NK fates: reprogramming into enriched memory-like (eML) NK cells or priming into effector conventional NK (effcNK) cells. eML NK cells had distinct transcriptional and epigenetic profiles and enhanced function, whereas effcNK cells resembled cytokine-primed cNK cells. Two transcriptionally discrete subsets of eML NK cells were also identified, eML-1 and eML-2, primarily arising from CD56bright or CD56dim mature NK cell subsets, respectively. Furthermore, these eML subsets were evident weeks after transfer of IL-12/15/18–activated NK cells into patients with cancer. Our findings demonstrate that NK cell activation with IL-12/15/18 results in previously unappreciated diverse cellular fates and identifies new strategies to enhance NK therapies. Editor's summary: Cytokine-induced memory-like (ML) natural killer (NK) cells are an attractive candidate for NK-based immunotherapies. To determine how cytokine stimulation epigenetically and transcriptionally regulates ML NK differentiation, Foltz et al. used multiomics to study interleukin-12/15/18–activated human NK cells. They identified a subset of enriched memory-like (eML) NK cells with unique epigenetic and transcriptional profiles and enhanced function. eML NK cells were composed of two transcriptionally distinct subsets, eML-1 and eML-2, that had unique features and origins. Furthermore, eML-1 and eML-2 populations were detected in patients with leukemia receiving ML NK cell therapy. These findings shed light on the molecular mechanisms governing cytokine-induced NK memory and may help to inform NK-based immunotherapies. —Hannah Isles [ABSTRACT FROM AUTHOR]

Accumulation of senescent cells (SNCs) with a senescence‐associated secretory phenotype (SASP) has been implicated as a major source of chronic sterile inflammation leading to many age‐related pathologies. Herein, we provide evidence that a bifunctional immunotherapeutic, HCW9218, with capabilities of neutralizing TGF‐β and stimulating immune cells, can be safely administered systemically to reduce SNCs and alleviate SASP in mice. In the diabetic db/db mouse model, subcutaneous administration of HCW9218 reduced senescent islet β cells and SASP resulting in improved glucose tolerance, insulin resistance, and aging index. In naturally aged mice, subcutaneous administration of HCW9218 durably reduced the level of SNCs and SASP, leading to lower expression of pro‐inflammatory genes in peripheral organs. HCW9218 treatment also reverted the pattern of key regulatory circadian gene expression in aged mice to levels observed in young mice and impacted genes associated with metabolism and fibrosis in the liver. Single‐nucleus RNA Sequencing analysis further revealed that HCW9218 treatment differentially changed the transcriptomic landscape of hepatocyte subtypes involving metabolic, signaling, cell‐cycle, and senescence‐associated pathways in naturally aged mice. Long‐term survival studies also showed that HCW9218 treatment improved physical performance without compromising the health span of naturally aged mice. Thus, HCW9218 represents a novel immunotherapeutic approach and a clinically promising new class of senotherapeutic agents targeting cellular senescence‐associated diseases. [ABSTRACT FROM AUTHOR]