Biology subjects

Newell, E.

Publications and source records attributed to Newell, E..

9 recordsLinked to original sources

bioRxiv2026

Human CD4 T cells coordinate antitumor immunity through indirect antigen presentation

Whether human tumor-specific CD4 T cells can drive antitumor immunity in cancers lacking tumor-cell MHC class II expression has not been established. In MHC class II-negative melanoma and breast cancer, CD4 T cells with a transcriptional signature of tumor specificity correlated with myeloid and CD8 T cell activation. Using a patient-derived NY-ESO-specific, HLA-DP04-restricted TCR, we tested whether human CD4 T cells could control tumors through indirect antigen presentation. In vitro, CD4 T cells inhibited HLA-DP-negative melanoma growth through recognition of tumor-derived antigen on antigen presenting cells (APC). In humanized mice, CD4 T cell transfer induced regression of HLA-DP-negative tumors, and control required HLA-matched human APCs. CD4 T cell transfer induced endogenous CD8 T cell proliferation and myeloid activation that mirrored immune programs correlated with the presence of these cells in patients. These findings establish that human tumor-specific CD4 T cells coordinate antitumor immunity through APC without direct tumor recognition, supporting their therapeutic relevance in MHC class II-negative cancers.

immunology↗

bioRxiv2025

Chorionic Gonadotropin Beta 7 is a marker of immune evasion in cancer

Human chorionic gonadotropin beta (beta-hCG) is an oncofetal antigen expressed by trophoblast cells of the placenta, with minimal expression in adult somatic tissues. Numerous studies have demonstrated that beta-hCG-encoding genes are expressed in various cancers, but expression of these genes (CGB3, CGB5, CGB7, and CGB8) across diverse cancers has not been systematically evaluated. Here, we report that CGB genes are more widely expressed across diverse cancer types than previously appreciated and that secreted beta-hCG is readily detected. In particular, CGB genes are expressed in the majority of urothelial bladder cancers, where CGB7 is most frequently expressed and significantly associated with an immunosuppressed tumor microenvironment, including decreased CD8+ T cell infiltration. Multiple CGB genes are associated with failure to respond to immune checkpoint inhibitor (ICI) therapy, and CGB7 is particularly strongly predictive of poor prognosis. Overall, our findings indicate that beta-hCG is a clinically accessible, predictive biomarker of immunotherapeutic response.

cancer biology↗

bioRxiv2023

Neuroprotective Effects of Naltrexone in a Mouse Model of Post-Traumatic Epilepsy

Traumatic Brain Injury (TBI) induces neuroinflammatory responses that can initiate epileptogenesis, which develops into epilepsy. Recently, we identified the anti-convulsive effects of naltrexone, a mu-opioid receptor (MOR) antagonist. While blocking opioid receptors can reduce inflammation, it is unclear if post-TBI epileptogenesis can be prevented by blocking MORs. Here, we tested if naltrexone prevents neuroinflammation and epileptogenesis post-TBI. TBI was induced by a modified Marmarau Weight-Drop (WD) method applied to four-week-old C57BL/6J male mice. Mice were given the pro-convulsant pentylenetetrazol (PTZ) on day two post-injury while telemetry-monitored mice received PTZ on day five. Naltrexone/vehicle treatment started two hours after PTZ. Integrated EEG-video (vEEG) recorded interictal events and spontaneous seizures for three months. Molecular, histological and neuroimaging techniques were used to evaluate neuroinflammation and neurodegeneration both acutely and chronically. Peripheral immune responses were assessed through serum chemokine/cytokine measurements. We observed increases in MOR expression, nitro-oxidative stress, mRNA expression of inflammatory cytokines, microgliosis, neurodegeneration, and white matter damage in the neocortex of TBI mice. vEEG revealed increased interictal events in TBI mice, with 71% developing epilepsy. Naltrexone ameliorated neuroinflammation and neurodegeneration, reduced interictal events and prevented epilepsy, illustrating that naltrexone is a promising drug to prevent TBI-associated neuroinflammation and epileptogenesis in post-traumatic epilepsy.

neuroscience↗

bioRxiv2022

MR1-restricted T cell clonotypes are associated with 'resistance' to M.tuberculosis infection

T cells are required for a protective immune response against the human adapted pathogen Mycobacterium tuberculosis (M.tb). We recently described a cohort of Ugandan household contacts of tuberculosis cases that appear to resist M.tb infection (RSTRs) and showed that these individuals harbor IFN-{gamma} independent T cell responses to M.tb-specific peptide antigens. However, T cells also recognize non-protein antigens via antigen presenting systems that are independent of genetic background, leading to their designation as donor-unrestricted T (DURT) cells. We used combinatorial tetramer staining and multi-parameter flow cytometry to comprehensively characterize the association between DURTs and resistance to M.tb infection. We did not observe a difference in peripheral blood frequencies of invariant natural killer T (iNKT) cells, germline encoded mycolyl-reactive (GEM) T cells, or {gamma}{delta} T cells between RSTRs and matched controls with latent M.tb infection (LTBIs). However, we did observe a 1.65-fold increase in frequency of circulating MR1-restricted T (MR1T) cells among RSTRs in comparison with LTBI (p=0.03). Multi-modal single cell RNA-sequencing of 18,251 MR1T cells sorted from a subset of donors revealed 5150 clonotypes that expressed a common transcriptional program, the majority of which were private. Deep sequencing of the TCR- repertoire revealed several DURT clonotypes that were expanded among RSTRs, including at least two MR1T clonotypes. Taken together, our data reveal unexpected donor-specific diversity in the TCR repertoire of human MR1T cells as well as associations between MR1 clonotypes and resistance to M.tb infection.

immunology↗

bioRxiv2021

Protracted yet coordinated differentiation of long-lived SARS-CoV-2-specific CD8+ T cells during COVID-19 convalescence

CD8+ T cells are important antiviral effectors that can potentiate long-lived immunity against COVID-19, but a detailed characterization of these cells has been hampered by technical challenges. We screened 21 well-characterized, longitudinally-sampled convalescent donors that recovered from mild COVID-19 against a collection of SARS-CoV-2 tetramers, and identified one participant with an immunodominant response against Nuc322-331, a peptide that is conserved in all the SARS-CoV-2 variants-of-concern reported to date. We conducted 38- parameter CyTOF phenotyping on tetramer-identified Nuc322-331-specific CD8+ T cells, and on CD4+ and CD8+ T cells recognizing the entire nucleocapsid and spike proteins from SARS- CoV-2, and took 32 serological measurements on longitudinal specimens from this participant. We discovered a coordination of the Nuc322-331-specific CD8+ T response with both the CD4+ T cell and antibody pillars of adaptive immunity. Nuc322-331-specific CD8+ T cells were predominantly central memory T cells, but continually evolved over a [~]6-month period of convalescence. We observed a slow and progressive decrease in the activation state and polyfunctionality of the Nuc322-331-specific CD8+ T cells, accompanied by an increase in their lymph-node homing and homeostatic proliferation potential. These results suggest that following a typical case of mild COVID-19, SARS-CoV-2-specific CD8+ T cells not only persist but continuously differentiate in a coordinated fashion well into convalescence, into a state characteristic of long-lived, self-renewing memory.

immunology↗

bioRxiv2020

Metformin enhances anti-mycobacterial responses by educating immunometabolic circuits of CD8+ T cells

Diabetic patients taking metformin have lower risk for Mycobacterium tuberculosis (Mtb) infection, progression from infection to tuberculosis (TB) disease, TB morality and TB recurrence. However, a detailed mechanistic understanding of metformins protective immunological benefits on host resistance to TB is lacking. In this study, using mass cytometry we show that metformin treatment expands memory-like antigen-inexperienced CD8+CXCR3+ T cells in naive mice, and in healthy and diabetic humans. Metformin-educated CD8+ T cells have increased (i) mitochondrial mass, oxidative phosphorylation, and fatty acid oxidation; (ii) survival capacity; and (iii) anti-mycobacterial properties. CD8+ T cells from CXCR3-/- mice did not exhibit metformin-mediated metabolic programming. In BCG-vaccinated mice and guinea pigs, metformin enhanced immunogenicity and protective efficacy against Mtb challenge. Collectively, our results demonstrate an important role of CD8+ T cells in metformin-derived host metabolic-fitness towards Mtb infection.

immunology↗

bioRxiv2019

Engineered niches support the development of human dendritic cells in humanized mice

Classical dendritic cells (cDCs) are rare sentinel cells specialized in the regulation of adaptive immunity. Modeling cDC development is both crucial to study cDCs and harness their potential in immunotherapy. Here we addressed whether cDCs could differentiate in response to trophic cues delivered by mesenchymal components of the hematopoietic niche where they physiologically develop and maintain. We found that expression of the membrane bound form of human FLT3L and SCF together with CXCL12 in a bone marrow mesenchymal stromal cell line is sufficient to induce the contact-dependent specification of both type 1 and type 2 cDCs from CD34+ hematopoietic stem and progenitor cells (HSPCs). Engraftment of these engineered mesenchymal stromal cells (eMSCs) together with CD34+ HSPCs creates an in vivo synthetic niche in the dermis of immunodeficient mice. Cell-to-cell contact between HSPCs and stromal cells within these organoids drive the local specification of cDCs and CD123+AXL+CD327+ pre/AS-DCs. cDCs generated in vivo display higher levels of resemblance with human blood cDCs unattained by in vitro generated subsets. Altogether, eMSCs provide a novel and unique platform recapitulating the full spectrum of cDC subsets enabling their functional characterization in vivo.

immunology↗

bioRxiv2019

CD38 is a good predictor of anti-PD-1 immunotherapy responsiveness in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-associated mortality in the world. However, with the associated low five-year survival and high recurrence rates, alternative treatment modalities specifically immunotherapy have been researched. A correlation between CD38+ tumour-infiltrating leukocyte (TIL) density and improved prognosis was found in a recent study. However, studies relating to CD38 expression in immune infiltrates within tumours are limited. In the present study, we confirmed the expression of CD38 on macrophages in HCC and determined the relationship between CD38+ leukocytes and lymphocytes and patient response to immunotherapy. Using immunohistochemistry, we analysed tissue samples obtained from 20 patients from Singapore with HCC prior to immunotherapy. Tumour infiltrating leukocytes expression within tumour were correlated to the responsiveness of patients to immunotherapy.\n\nExpression of CD38 was found within the tumour cells and surrounding immune infiltrates including lymphocytes and macrophages. We then ask whether CD38 expression by the distinct cell populations may acquire theranostic relevance. Patients with higher level of CD38+ immune infiltrate subsets had significantly better response to anti-PD-1 immunotherapy, and this is also true for CD38+ lymphocytes within the tumour microenvironment. In particular, a cut-off of 13.0% positive out of total leukocytes and 12.4% positive out of total lymphocytes is found to be of strong predictive value of responsiveness to immunotherapy treatment, thus a strong theranostic impact is seen by using CD38 as a biomarker for anti-PD-1 therapy.\n\nThe establishment of an association between CD38 expression and the response to anti-PD-1 immunotherapy in HCC, could be applied to a larger cohort outside Singapore. These may eventually change the routine testing in clinical practice to identify HCC patients suitable for immunotherapy.

cancer biology↗

bioRxiv2018

Reverse-engineering flow-cytometry gating strategies for phenotypic labelling and high-performance cell sorting

MotivationRecent flow and mass cytometers generate 1,000,000 single cell datasets of dimensions 20 to 40. Many tools facilitate the discovery of new cell populations associated with diseases or physiology. These discoveries require the identification of new gating strategies, but gating strategies become exponentially harder to optimize when dimensionality increases. To facilitate this step we developed Hypergate, an algorithm which given a cell population of interest identifies a gating strategy optimized for high yield and purity.\n\nResultsHypergate achieves higher yield and purity than human experts, Support Vector Machines and Random-Forests on public datasets. We use it to revisit some established gating strategies for the identification of Innate lymphoid cells, which identifies concise and efficient strategies that allow gating these cells with fewer parameters but higher yield and purity than the current standards. For phenotypic description, Hypergates outputs are consistent with fields knowledge and sparser than those from a competing method.\n\nAvailability and ImplementationHypergate is implemented in R and available at http://github.com/ebecht/hypergate under an Open Source Initiative-compliant licence.

bioinformatics↗