HuR-dependent NK cell expansion is required for control of solid tumors and long-term virus infection
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ABSTRACT:
PROVIDER: PRJNA898792 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22206355_1.fastq.gz | Fastqsanger.gz | |||
| SRR22206355_2.fastq.gz | Fastqsanger.gz | |||
| SRR22206356_1.fastq.gz | Fastqsanger.gz | |||
| SRR22206356_2.fastq.gz | Fastqsanger.gz | |||
| SRR22206357_1.fastq.gz | Fastqsanger.gz |
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Project description:Natural Killer (NK) cells are innate lymphocytes capable of controlling tumors and virus infections through direct lysis and cytokine production. NK cells also expand and accumulate in affected tissues, but the role of NK cell expansion in tumor and viral control is not well understood. Here, we describe that post-transcriptional regulation by the RNA-binding protein HuR is essential for NK cell expansion, without overtly affecting NK cell effector functions. HuR-dependent NK cell expansion facilitated control of solid tumors, but it was dispensable for control of tumor metastases. In virus infection, HuR-dependent NK cell expansion contributed to long-term viral control in the absence of adaptive immunity without affecting acute infection. HuR-deficient NK cells displayed defects in expression of and splicing in cell cycle-associated genes, including decreased expression and alternative splicing of Ska2, a component of the spindle and kinetochore complex that is involved in chromosome separation during cell division. Furthermore, we identified an essential role for SKA2 in NK cell expansion. These results show that post-transcriptional regulation by HuR specifically affects NK cell expansion which is required for control of several solid tumors and long-term virus infection.
2023-08-31 | GSE217392 | GEO
Project description:Natural killer (NK) cells are lymphocytes capable of controlling tumors and virus infections through direct lysis and cytokine production. While both T and NK cells expand and accumulate in affected tissues, the role of NK cell expansion in tumor and viral control is not well understood. Here, we show that posttranscriptional regulation by the RNA-binding protein HuR is essential for NK cell expansion without negatively affecting effector functions. HuR-deficient NK cells displayed defects in the metaphase of the cell cycle, including decreased expression and alternative splicing of Ska2, a component of the spindle and kinetochore complex. HuR-dependent NK cell expansion contributed to long-term cytomegalovirus control and facilitated control of subcutaneous tumors but not tumor metastases in two independent tumor models. These results show that posttranscriptional regulation by HuR specifically affects NK cell expansion, which is required for the control of long-term virus infection and solid tumors, but not acute infection or tumor metastases, highlighting fundamental differences with antigen-specific T cell control.
| S-EPMC10497399 | biostudies-literature
Project description:Chimeric antigen receptor (CAR)-natural killer (NK) cell therapies hold promise for solid tumors but remain limited by poor tumor infiltration, persistence, and resistance within the tumor microenvironment (TME). To identify gain-of-function (GOF) targets that enhance CAR-NK efficacy, we performed an unbiased in vivo Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) activation (CRISPRa) screen, followed by a barcoded targeted in vivo open reading frame (ORF) screen in primary human CAR-NK cells. We identified, and robustly validated OR7A10, a G protein-coupled receptor (GPCR), as the top candidate. Engineering CAR-NKs with OR7A10 cDNA, a CRISPR-independent method with simple manufacturing strategy, enhanced proliferation, activation, degranulation, cytokine production, death ligand expression, chemokine receptor expression, cytotoxicity, persistence, metabolic fitness, and TME resistance, while reducing exhaustion in primary human NK cells derived from multiple peripheral blood and cord blood donors. OR7A10-GOF CAR-NKs displayed robust in vivo efficacy across multiple solid tumor models, achieving a 100% complete response in an orthotopic breast cancer model with long term tumor control and survival benefit. These findings establish OR7A10-engineered CAR-NKs as a highly potent and scalable off-the-shelf therapeutic for solid tumors.
2025-12-17 | GSE310267 | GEO
Project description:Ex vivo activation and expansion of natural killer (NK) cells is a strategy to produce sufficient numbers of these effector cells for adoptive immunotherapy. Therefore we aimed at the development of an automated, clinical scale NK cell expansion process and compared NK cells after manual and automated expansion.We found only a small subset of 124 genes that significantly varied between both sample groups. These genes were associated with movement of leukocytes were identified including a group of genes for NK cell movement (CMKLR1, CX3CR1, S1PR5, GNLY and CXCR1) which were slightly higher expressed after automated compared to manual expansion. Nevertheless, the expansion profiles of NK cells after automated or manual expansion were rather similar in comparison to the remarkable difference between primary and expanded NK cells in general represented by the vast majority of regulated genes between the analyzed sample groups. Pathway analysis revealed that most of regulated genes upon expansion were associated with cell cycle regulation, DNA replication, DNA recombination and DNA repair, regulation of apoptosis and cell survival as well as cytokine signaling. Furthermore, the expression of many NK cell relevant markers was changed upon expansion with the strongest effects on up regulation of TRAIL and FASL, inhibitory TIGIT and chemokine receptors CCR2, CCR5 and CXCR6. In addition, granzyme M was down regulated but other important effector molecules like TNFa, perforin and granzymes A, B and K were up regulated. In summary we could show that manual and automatically expanded NK cells show a similar expansion profile while the differ significantly from primary NK cells. Up regulation of many NK cell relevant markers indicate for an enhanced NK cell functionaility after ex vivo activation and expansion. 24 samples were analyzed in total. 6 biological replicates represented by cells from different donors. 4 different samples per donor: freshly isolated NK cells (d0) and NK cells expanded for 14 days under 3 different conditions: in co-culture with EBV-LCL feeder cells and 500 U/mL IL2 either cultivated manually in T75 flasks (T) or automatically using the CliniMACS Prodigy system (P); NK cells cultured with 500 U/ml IL2 without feeder cells (I)
2015-04-23 | E-GEOD-62654 | biostudies-arrayexpress
Project description:NK cell expansion on uAPC helper cells
| PRJNA682740 | ENA
Project description:Natural killer (NK) cells are critical for the immune response to cancer. However, solid tumor-infiltrating NK cells display reduced persistence and effector functions, limiting their clinical efficacy. To understand the mechanisms that induce human NK cell dysfunction in solid tumors, we compared single-cell gene expression in patient-matched tumor-infiltrating compared to tumor-adjacent NK cells to identify unfolded protein response (UPR) genes associated with worse cancer patient survival. Primary human NK cells accumulated unfolded proteins and induced a chronic UPR response to nutrient stress from the tumor microenvironment metabolome (TMM), sufficient to cause pronounced dysfunction and decreased persistence. Mechanistically, the transcription factor Fli1 epigenetically repressed UPR genes to limit human NK cell proteostasis in the presence of the TMM. CRISPR-mediated Fli1 deletion enhanced unfolded protein clearance, persistence, and tumor control in vivo. Thus, our results suggest that the TMM is sufficient to induce human NK cell dysfunction in solid tumors through the regulation of proteostasis.
2026-02-10 | GSE296353 | GEO
Project description:Natural killer (NK) cells are critical for the immune response to cancer. However, solid tumor-infiltrating NK cells display reduced persistence and effector functions, limiting their clinical efficacy. To understand the mechanisms that induce human NK cell dysfunction in solid tumors, we compared single-cell gene expression in patient-matched tumor-infiltrating compared to tumor-adjacent NK cells to identify unfolded protein response (UPR) genes associated with worse cancer patient survival. Primary human NK cells accumulated unfolded proteins and induced a chronic UPR response to nutrient stress from the tumor microenvironment metabolome (TMM), sufficient to cause pronounced dysfunction and decreased persistence. Mechanistically, the transcription factor Fli1 epigenetically repressed UPR genes to limit human NK cell proteostasis in the presence of the TMM. CRISPR-mediated Fli1 deletion enhanced unfolded protein clearance, persistence, and tumor control in vivo. Thus, our results suggest that the TMM is sufficient to induce human NK cell dysfunction in solid tumors through the regulation of proteostasis.
2026-02-10 | GSE296352 | GEO
Project description:Natural killer (NK) cells are critical for the immune response to cancer. However, solid tumor-infiltrating NK cells display reduced persistence and effector functions, limiting their clinical efficacy. To understand the mechanisms that induce Mouse NK cell dysfunction in solid tumors, we compared single-cell gene expression in patient-matched tumor-infiltrating compared to tumor-adjacent NK cells to identify unfolded protein response (UPR) genes associated with worse cancer patient survival. Primary Mouse NK cells accumulated unfolded proteins and induced a chronic UPR response to nutrient stress from the tumor microenvironment metabolome (TMM), sufficient to cause pronounced dysfunction and decreased persistence. Mechanistically, the transcription factor Fli1 epigenetically repressed UPR genes to limit Mouse NK cell proteostasis in the presence of the TMM. CRISPR-mediated Fli1 deletion enhanced unfolded protein clearance, persistence, and tumor control in vivo. Thus, our results suggest that the TMM is sufficient to induce Mouse NK cell dysfunction in solid tumors through the regulation of proteostasis.
2026-02-10 | GSE296356 | GEO
Project description:Natural killer (NK) cells are critical for the immune response to cancer. However, solid tumor-infiltrating NK cells display reduced persistence and effector functions, limiting their clinical efficacy. To understand the mechanisms that induce Mouse NK cell dysfunction in solid tumors, we compared single-cell gene expression in patient-matched tumor-infiltrating compared to tumor-adjacent NK cells to identify unfolded protein response (UPR) genes associated with worse cancer patient survival. Primary Mouse NK cells accumulated unfolded proteins and induced a chronic UPR response to nutrient stress from the tumor microenvironment metabolome (TMM), sufficient to cause pronounced dysfunction and decreased persistence. Mechanistically, the transcription factor Fli1 epigenetically repressed UPR genes to limit Mouse NK cell proteostasis in the presence of the TMM. CRISPR-mediated Fli1 deletion enhanced unfolded protein clearance, persistence, and tumor control in vivo. Thus, our results suggest that the TMM is sufficient to induce Mouse NK cell dysfunction in solid tumors through the regulation of proteostasis.
2026-02-10 | GSE296354 | GEO
Project description:Natural killer (NK) cells are critical for the immune response to cancer. However, solid tumor-infiltrating NK cells display reduced persistence and effector functions, limiting their clinical efficacy. To understand the mechanisms that induce human NK cell dysfunction in solid tumors, we compared single-cell gene expression in patient-matched tumor-infiltrating compared to tumor-adjacent NK cells to identify unfolded protein response (UPR) genes associated with worse cancer patient survival. Primary human NK cells accumulated unfolded proteins and induced a chronic UPR response to nutrient stress from the tumor microenvironment metabolome (TMM), sufficient to cause pronounced dysfunction and decreased persistence. Mechanistically, the transcription factor Fli1 epigenetically repressed UPR genes to limit human NK cell proteostasis in the presence of the TMM. CRISPR-mediated Fli1 deletion enhanced unfolded protein clearance, persistence, and tumor control in vivo. Thus, our results suggest that the TMM is sufficient to induce human NK cell dysfunction in solid tumors through the regulation of proteostasis.
2026-02-10 | GSE296351 | GEO