Yapeng Su's research while affiliated with Fred Hutchinson Cancer Research Center and other places

Publications (73)

Article
Full-text available
The influence of metabolism on signaling, epigenetic markers, and transcription is highly complex yet important for understanding cancer physiology. Despite the development of high-resolution multi-omics technologies, it is difficult to infer metabolic activity from these indirect measurements. Fortunately, genome-scale metabolic models and constra...
Article
Background: Less than half of ovarian cancer patients survive five years after diagnosis. This rate has changed little in the last 30 years, highlighting the need for novel therapies. A promising new strategy with the potential to control tumor growth without toxicity to healthy tissues employs immune T cells engineered to target proteins uniquely...
Article
Here we find that CD8 ⁺ T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49 ⁺ CD8 ⁺ regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8 ⁺ T cells efficiently eliminated pathogenic gliadin-spec...
Article
Full-text available
Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, a...
Article
Full-text available
A better understanding of the metabolic alterations in immune cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may elucidate the wide diversity of clinical symptoms experienced by individuals with coronavirus disease 2019 (COVID-19). Here, we report the metabolic changes associated with the peripheral immune respo...
Article
Full-text available
Cross-reactivity and direct killing of target cells remain underexplored for SARS-CoV-2 specific CD8+ T cells. Isolation of T cell receptors (TCRs) and overexpression in allogeneic cells allows for extensive T cell reactivity profiling. We identify SARS-CoV-2 RNA-dependent RNA-polymerase (RdRp/NSP12) as highly conserved likely due to its critical r...
Preprint
Previous reports show that Ly49 ⁺ CD8 ⁺ T cells can suppress autoimmunity in mouse models of autoimmune diseases. Here we find a markedly increased frequency of CD8 ⁺ T cells expressing inhibitory Killer cell Immunoglobulin like Receptors (KIR), the human equivalent of the Ly49 family, in the blood and inflamed tissues of various autoimmune disease...
Article
Background Over 20,000 women are diagnosed with ovarian cancer annually, and more than half will die within 5 years. This rate has changed little in the last 20 years, highlighting the need for therapy innovation. A promising new strategy with the potential to control tumor growth without toxicity to healthy tissues employs immune T cells engineere...
Article
Longitudinal analyses of the innate immune system including earliest time points are essential to understand the immunopathogenesis and clinical course of COVID-19. Here, we performed a detailed characterization of natural killer cells in 205 patients (403 samples, day 2-41 after symptom onset) from four independent cohorts using single-cell transc...
Preprint
Full-text available
The immunological picture of how different patients recover from COVID-19, and how those recovery trajectories are influenced by infection severity, remain unclear. We investigated 140 COVID-19 patients from diagnosis to convalescence using clinical data, viral load assessments, and multi-omic analyses of blood plasma and circulating immune cells....
Article
Full-text available
Viral infections induce a conserved host response distinct from bacterial infections. We hypothesized that the conserved response is associated with disease severity and is distinct between patients with different outcomes. To test this, we integrated 4,780 blood transcriptome profiles from patients aged 0 to 90 years infected with one of 16 viruse...
Preprint
Full-text available
SARS-CoV-2 pandemic, the fourth pandemic of the decade, has underscored gaps in global pandemic preparedness and the need for generalizable tests to avert overwhelming healthcare systems worldwide, irrespective of a virus. We integrated 4,780 blood transcriptome profiles from patients infected with one of 16 viruses across 34 independent cohorts fr...
Article
Full-text available
We present an integrated analysis of the clinical measurements, immune cells, and plasma multi-omics of 139 COVID-19 patients representing all levels of disease severity, from serial blood draws collected during the first week of infection following diagnosis. We identify a major shift between mild and moderate disease, at which point elevated infl...
Preprint
Full-text available
Recovery from COVID-19 is associated with production of anti-SARS-CoV-2 antibodies, but it is uncertain whether these confer immunity. We describe viral RNA shedding duration in hospitalized patients and identify patients with recurrent shedding. We sequenced viruses from two distinct episodes of symptomatic COVID-19 separated by 144 days in a sing...
Article
Full-text available
Non-invasively probing metabolites within single live cells is highly desired but challenging. Here we utilize Raman spectro-microscopy for spatial mapping of metabolites within single cells, with the specific goal of identifying druggable metabolic susceptibilities from a series of patient-derived melanoma cell lines. Each cell line represents a d...
Article
Full-text available
Glycogen, a branched glucose polymer, helps regulate glucose homeostasis through immediate storage and release of glucose. Re-programming of glycogen metabolism has recently been suggested to play an emerging role in cancer progression and tumorigene-sis. However, regulation of metabolic rewiring for glycogen synthesis and breakdown in cancer cells...
Conference Paper
p>Integrated proteomic and metabolic single-cell assays reveal multiple independent adaptive responses to drug tolerance in a BRAF-mutant melanoma cell line Cancers commonly develop resistance against chemotherapeutics or targeted therapies through various types of genetic or non-genetic mechanisms. Non-genetic mechanisms have been shown to occur...
Conference Paper
We utilized Raman spectro-microscopy to non-invasively probe metabomics within single live cells, aiming to identify druggable metabolic susceptibilities from a series of patient-derived BRAF mutant melanoma cell lines. Each cell line represents a phenotype with different characteristic level of de-differentiation and BRAFi (BRAF inhibitor) resista...
Preprint
Full-text available
Host immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of PBMCs in which whole transcriptome, 192 surface proteins, and T a...
Article
Full-text available
The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge for understanding biological changes ranging from cellular differentiation to epigenetic responses of diseased cells upon drugging. We integrate experiments and theory to determine the trajectories that single BRAFV600E mutant m...
Article
The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge, with relevance towards understanding biological changes ranging from cellular differentiation to epigenetic (adaptive) responses of diseased cells to drugging. We report on a combined experimental and theoretic method for deter...
Preprint
The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge, with relevance towards understanding biological changes ranging from cellular differentiation to epigenetic (adaptive) responses of diseased cells to drugging. We report on a combined experimental and theoretic method for deter...
Article
Full-text available
Neoantigen-specific T cells are increasingly viewed as important immunotherapy effectors, but physically isolating these rare cell populations is challenging. Here, we describe a sensitive method for the enumeration and isolation of neoantigen-specific CD8+ T cells from small samples of patient tumor or blood. The method relies on magnetic nanopart...
Article
We resolved a mechanism connecting tumor epigenetic plasticity with non-genetic adaptive resistance to therapy, with MAPK inhibition of BRAF-mutant melanomas providing the model. These cancer cells undergo multiple, reversible drug-induced cell-state transitions, ultimately yielding a drug-resistant mesenchymal-like phenotype. A kinetic series of t...
Preprint
Full-text available
We resolved a mechanism connecting tumor epigenetic plasticity with non-genetic adaptive resistance to therapy, with MAPK inhibition of BRAF-mutant melanomas providing the model. These cancer cells undergo multiple, reversible drug-induced cell-state transitions, ultimately yielding a drug-resistant mesenchymal-like phenotype. A kinetic series of t...
Article
Full-text available
Phenotypic plasticity is associated with non-genetic drug tolerance in several cancers. Such plasticity can arise from chromatin remodeling, transcriptomic reprogramming, and/or protein signaling rewiring, and is characterized as a cell state transition in response to molecular or physical perturbations. This, in turn, can confound interpretations...
Article
Full-text available
T cell receptor (TCR) ligand discovery is essential for understanding and manipulating immune responses to tumors. We developed a cell-based selection platform for TCR ligand discovery that exploits a membrane transfer phenomenon called trogocytosis. We discovered that T cell membrane proteins are transferred specifically to target cells that prese...
Article
Biological function arises from the interplay of proteins, transcripts, and metabolites. An ongoing revolution in miniaturization technologies has created tools to analyze any one of these species in single cells, thus resolving the heterogeneity of tissues previously invisible to bulk measurements. An emerging frontier is single cell multi-omics,...
Conference Paper
Cancers commonly develop resistance against chemotherapeutics or targeted therapies through either genetic mechanism or adaptive responses that commonly involve epigenetic reprogramming and activation of compensatory signaling pathways. Recent examples of such an adaptive response involve the treatment of BRAF mutant melanoma cancer patients with i...
Article
Deregulation of several microRNAs (miRs) can influence critical developmental checkpoints during hematopoiesis as well as cell functions, eventually leading to the development of autoimmune disease or cancer. We found that miR-125b is expressed in bone marrow multipotent progenitors and myeloid cells but shut down in the B-cell lineage, and the gen...
Article
Full-text available
For adoptive cell transfer (ACT) immunotherapy of tumor-reactive T cells, an effective therapeutic outcome depends upon cell dose, cell expansion in vivo through a minimally differentiated phenotype, long term persistence, and strong cytolytic effector function. An incomplete understanding of the biological coupling between T cell expansion, differ...
Data
Tumor infiltrating lymphocytes (TIL) characterization. (DOCX)
Data
In vivo antitumor efficacy with peptide control vs. selected conditions in Fig 2. For the peptide control, OVA peptide and IL2 were added directly to the splenocytes (details in Methods section), along with antigen-presenting cells. In the tetramer stimulation, tetramer and anti-CD28 were used as the molecular stimulation. Values plotted are mean ±...
Data
Enriched biological processes of OT1 CD8+ T cells from transcriptome analysis as T1 is increased. The bar graphs show differences between 16 hrs and 10 min, and 16 hrs and 4 hrs. (DOCX)
Data
Enriched transcriptional network of human CD8+ T cells from transcriptome analysis. A. Differential expressed genes relative to the 0-hour (NS) T1 conditioning are displayed with self-organizing map. B. Transcription factors that are enriched with the most dramatically up-regulated genes as T1 is increased from 0 hour (non-stimulated) to 2 hours. (...
Data
Population of OT1+ cells that infiltrate into the tumor site. Flow cytometric determination of OT1+ T cells in mouse tumor biopsy 4 days after ACT of OT1 T cells with 16-hour T1 conditioning with molecular stimulation (OT1 tetramer + anti-CD28), or no stimulation. (DOCX)
Data
Quantification of CD137 staining. The total area (means ± s.e.m) was quantified using an intensity threshold. Analysis was done by one-way ANOVA followed by Bonferroni’s multiple comparison test (**: P < 0.01). The quantification was based on 4 fields per section (n = 4–6 histological sections per animal; 4–5 animals per group). (DOCX)
Data
Cytokine secretion dynamics and calibration curve. A. Characterization of secreted cytokines (CCL3 (upper) and IL2 (lower)) for OT1 T cells with molecular stimulation (OT1 tetramer + anti-CD28 + PMA + Ionomycin) under different cell densities (higher: 5 × 105/ml, lower: 2 × 105/ml) as T1 increases. B. Calibration curve of fluorescence signal vs. pr...
Data
Relative number of cells that secrete a particular cytokine for human CD4+ T cells. The secretion profile is largely similar for various T1 conditioning time. The absolute number of cells that secrete and the average secretion intensity, however, are significantly increased as T1 increases (shown in the main text). (DOCX)
Data
List of antibody panel for human T cells in single cell barcode chip (SCBC). (DOCX)
Data
List of antibody panel used for flow cytometry immuno-phenotyping analysis for human patient sample. (DOCX)
Data
Cell clustering dynamics with strong molecular stimulation (OT1 tetramer + anti-CD28 + PMA + ionomycin). Representative images of the clustering area under different cell densities (upper: 2 × 105/ml, lower: 5 × 105/ml). Scale bar = 200 μm. (DOCX)
Data
Phenotype dynamics of antigen specific OT1 CD8+ T cells. Histogram presentation of the expression level of surface markers CD62L, CD44 and KLRG1 as T1 increases from non-stimulated (n.s.) to T1 = 4 hours to T1 = 16 hours. (DOCX)
Data
List of antibody panel for mouse T cells in SCBC. (DOCX)
Data
Ensemble cytokine secretion detection. (DOCX)
Data
Transcriptome dynamics of OT1 CD8+ T cells. A. A heatmap of the sequenced genes indicates a distinct and evolving gene expression profile as T1 increases. Color bar, mean (black) above (red) and below (blue) standard deviation. Representative cytokine genes including IL2 (B), CCL3 (C) and TNF (D) and surface marker for activation (CD69 (E) and CD44...
Data
Gene dynamics of OT1 CD8+ T cells that are highly correlated with effector-vs-memory regulation. The dynamic change of genes up-regulated in comparison of effector CD8 T cells versus memory CD8 T cells as a function of T1 represented by heatmap (A) and GATE self-organizing map (B). The dynamics genes down-regulated in comparison to effector CD8 T c...
Data
Flow cytometry analysis of mouse samples. (DOCX)
Data
Gross cell morphology of EG.7 tumor 4 days after ACT under various conditions. Hematoxylin staining demonstrates increased number of apoptotic cells that are shrunken with pyknotic and fragmented nuclei and condense cytoplasm after adoptive transfer of CD8+ T cells under 16-hour T1 conditioning with Ova tetramer and anti-CD28 stimulation (A) compar...
Data
Ensemble cytokine secretion during T1 = 16 h for different molecular stimulation (anti-CD3 + anti-CD28, left) and (OT1 tetramer + anti-CD28). (DOCX)
Data
Enriched transcriptional network of OT1 CD8+ T cells from transcriptome analysis. A. Differential expressed genes relative to the 10 mins T1 conditioning are displayed with self-organizing map. In this map, each pixel represents a minicluster of genes. The organization of the map is based on all gene expression data sets (at all time points). Genes...
Data
Enriched biological processes of human CD8+ T cells from transcriptome analysis as T1 is increased from 0 hour (NS) to 2 hours (A) and from 2 hours to 4 hours (B). (DOCX)
Data
Enlarged luciferase images displayed in Fig 2C. (DOCX)
Data
Enriched transcription factors (A) and biological processes (B) by genes that are regulated in the same way in comparison of effector CD8 T cells versus memory CD8 T cells as T1 increases. Enriched transcription factors (C) and Biological processes (D) by genes that are regulated in the opposite way in comparison of effector CD8 T cells versus memo...
Data
Correlation of human (A) CD4+ and (B) CD8+ T cells from the same patient as T1 increases from 0 hour (NS) to 4 hours. (DOCX)
Data
Enriched transcription factors (A) and biological processes (B) by genes that are regulated in the same way in comparison of effector CD8 T cells versus memory CD8+ T cells as T1 increases. (DOCX)
Data
The level of proliferation in EG.7 tumor after 4 days after ACT under various conditions. Ki67 staining demonstrates decreased numbers of proliferating cells after adoptive transfer of CD8+ T cells under 16-hour T1 conditioning with Ova tetramer and anti-CD28 stimulation (A) compared to non-stimulated CD8+ T cells (B) and without adoptive T cell tr...
Data
The RNA expression level of IL2 receptor (IL2RA) as a function of T1 conditioning time. A consistent elevation was observed for OT1 CD8+ T cells, human CD4+ and CD8+ T cells. (DOCX)
Data
Phenotypic evolution and transcriptome dynamics for human CD4+ T cells after various T1 conditioning time. A. Phenotype analysis from multi-color flow cytometry of CD4+ T cells shows loss of the naïve phenotype, but no evidence of terminal differentiation. B. The expression level of naïve-associated (upper) and effector-associated (lower) genes as...
Data
Gene dynamics of human CD8+ T cells that are highly correlated with effector-vs-memory regulation. The dynamic change of genes up-regulated in comparison of effector CD8 T cells versus memory CD8 T cells as a function of T1 represented by heatmap (A) and GATE self-organizing map (B). The dynamic change of genes down-regulated in comparison of effec...
Article
Full-text available
Neoantigen-specific T cells are increasingly viewed as important immunotherapy effectors, but physically isolating these rare cell populations is challenging. Here, we describe a sensitive method for the enumeration and isolation of neoantigen-specific CD8+ T cells from small samples of patient tumor or blood. The method relies on magnetic nanopart...
Article
Continuous BRAF inhibition of BRAF mutant melanomas triggers a series of cell state changes that lead to therapy resistance and escape from immune control before establishing acquired resistance genetically. We used genome-wide transcriptomics and single-cell phenotyping to explore the response kinetics to BRAF inhibition for a panel of patient-der...
Article
New insights on cellular heterogeneity in the last decade provoke the development of a variety of single cell omics tools at a lightning pace. The resultant high-dimensional single cell data generated by these tools require new theoretical approaches and analytical algorithms for effective visualization and interpretation. In this review, we briefl...
Article
Targeted therapy that inhibits the BRAF (V600E) protein has shown impressive initial responses in metastatic melanoma patients. However, acquired drug resistance, derived from tumor heterogeneity, always limits its efficacy and compromises its treatment outcomes. Melanocyte to neural crest transition (MNT) has been observed to play crucial role in...
Article
Intratumoral heterogeneity of signaling networks may contribute to targeted cancer therapy resistance, including in the highly lethal brain cancer glioblastoma (GBM). We performed single-cell phosphoproteomics on a patient-derived in vivo GBM model of mTOR kinase inhibitor resistance and coupled it to an analytical approach for detecting changes in...
Article
We describe a supramolecular surface competition assay for quantifying glutamine uptake from single cells. Cy3-labeled cyclodextrins were immobilized on a glass surface as a supramolecular host/FRET donor, and adamantane-BHQ2 conjugates were employed as the guest/quencher. An adamantane-labeled glutamine analog was selected through screening a libr...
Article
The technology boom of single-cell metabolomics and proteomics has led to exciting biological discoveries in the past decade. It has become widely acknowledged that resolving the intratumoral heterogeneity at single cell resolution can aid the understanding of cancer therapeutic response and progression, as well as facilitate the development of the...