Biology subjects

Beynor, J. I.

Publications and source records attributed to Beynor, J. I..

4 recordsLinked to original sources

bioRxiv2024

Divergent response to radio-immunotherapy is defined by intrinsic features of the tumor microenvironment

BackgroundTreatment with immunotherapy can elicit varying responses across cancer types, and the mechanistic underpinnings that contribute to response vs. progression remain poorly understood. However, to date there are few preclinical models that accurately represent these disparate disease scenarios. MethodsUsing combinatorial radio-immunotherapy consisting of PD-1 blockade, IL2R{beta}{gamma} biased signaling, and OX40 agonism we were able to generate preclinical tumor models with conflicting responses, where head and neck squamous cell carcinoma (HNSCC) models responds and pancreatic ductal adenocarcinoma (PDAC) progresses. ResultsBy modeling these disparate states, we find that regulatory T cells (Tregs) are expanded in PDAC tumors undergoing treatment, constraining tumor reactive CD8 T cell activity. Consequently, the depletion of Tregs restores the therapeutic efficacy of our treatment and abrogates the disparity between models. Moreover, we show that through heterotopic implantations that the site of tumor development defines the response to therapy, as implantation of HNSCC tumors into the pancreas resulted in comparable levels of tumor progression. ConclusionsThis work highlights complexity of combining immunotherapies within the tumor microenvironment and further defines the immune and non-immune components of the tumor microenvironment as an intrinsic feature of immune suppression. What is already known on this topicO_LIIn Head and neck squamous cell carcinomas (HNSCC) and pancreatic ductal adenocarcinoma (PDAC), targeting PD-1 and IL2R{beta}{gamma} simultaneously (PD1-IL2v) has been shown to be effective when combined with radiation therapy (RT), yet complete response is still limited. The T cell co-stimulatory receptor OX40 (TNFRSF4) has pleiotropic effects, promoting T cell survival, expansion, and memory differentiation in conventional effector T cells, while subsequently limiting regulatory T cell (Treg) suppression by constraining induction and expression of Foxp3. Expression of OX40 is highly upregulated after treatment with PD1-IL2v, and we postulated that combining OX40 agonism with PD1-IL2v and RT would provide additional benefit. C_LI What this study addsO_LIUsing orthotopic models of HNSCC and PDAC, we found that the addition of OX40 agonism unexpectedly drives tumor progression in PDAC, but not HNSCC. Intriguingly, this effect dependent on the tumor microenvironment as the effect is reversed by swapping the location of tumor implantation. This progression was also abrogated by the depletion of regulatory T cells (Tregs), a known mediator of resistance in these models. C_LI How this study might affect research, practice or policyO_LIOur data demonstrate that unexpected and deleterious effects can stem from combining multiple immunotherapies. These findings hold particular translational relevance as the use of combination immunotherapies is increasingly common on trial. C_LI

immunology↗

bioRxiv2021

Modeling memory T cell states at single-cell resolution identifies in vivo state-dependence of eQTLs influencing disease

Many non-coding genetic variants cause disease by modulating gene expression. However, identifying these expression quantitative trait loci (eQTLs) is complicated by gene-regulation differences between cell states. T cells, for example, have fluid, multifaceted functional states in vivo that cannot be modeled in eQTL studies that aggregate cells. Here, we modeled T cell states and eQTLs at single-cell resolution. Using >500,000 resting memory T cells from 259 Peruvians, we found over one-third of the 6,511 cis-eQTLs had state-dependent effects. By integrating single-cell RNA and surface protein measurements, we defined continuous cell states that explained more eQTL variation than discrete states like CD4+ or CD8+ T cells and could have opposing effects on independent eQTL variants in a locus. Autoimmune variants were enriched in cell-state-dependent eQTLs, such as a rheumatoid-arthritis variant near ORMDL3 strongest in cytotoxic CD8+ T cells. These results argue that fine-grained cell state context is crucial to understanding disease-associated eQTLs.

genetics↗

bioRxiv2020

IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 and other diseases with tissue inflammation

Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. Using an integrative strategy, we built a reference by meta-analyzing > 300,000 immune cells from COVID-19 and 5 inflammatory diseases including rheumatoid arthritis (RA), Crohns disease (CD), ulcerative colitis (UC), lupus, and interstitial lung disease. Our cross-disease analysis revealed that an FCN1+ inflammatory macrophage state is common to COVID-19 bronchoalveolar lavage samples, RA synovium, CD ileum, and UC colon. We also observed that a CXCL10+ CCL2+ inflammatory macrophage state is abundant in severe COVID-19, inflamed CD and RA, and expresses inflammatory genes such as GBP1, STAT1, and IL1B. We found that the CXCL10+ CCL2+ macrophages are transcriptionally similar to blood-derived macrophages stimulated with TNF- and IFN-{gamma} ex vivo. Our findings suggest that IFN-{gamma}, alongside TNF-, might be a key driver of this abundant inflammatory macrophage phenotype in severe COVID-19 and other inflammatory diseases, which may be targeted by existing immunomodulatory therapies.

genomics↗

bioRxiv2020

Multimodal memory T cell profiling identifies a reduction in a polyfunctional Th17 state associated with tuberculosis progression

Mycobacterium tuberculosis (M.tb) results in 10 million active tuberculosis (TB) cases and 1.5 million deaths each year1, making it the worlds leading infectious cause of death2. Infection leads to either an asymptomatic latent state or TB disease. Memory T cells have been implicated in TB disease progression, but the specific cell states involved have not yet been delineated because of the limited scope of traditional profiling strategies. Furthermore, immune activation during infection confounds underlying differences in T cell state distributions that influence risk of progression. Here, we used a multimodal single-cell approach to integrate measurements of transcripts and 30 functionally relevant surface proteins to comprehensively define the memory T cell landscape at steady state (i.e., outside of active infection). We profiled 500,000 memory T cells from 259 Peruvians > 4.7 years after they had either latent M.tb infection or active disease and defined 31 distinct memory T cell states, including a CD4+CD26+CD161+CCR6+ effector memory state that was significantly reduced in patients who had developed active TB (OR = 0.80, 95% CI: 0.73-0.87, p = 1.21 x 10-6). This state was also polyfunctional; in ex vivo stimulation, it was enriched for IL-17 and IL-22 production, consistent with a Th17-skewed phenotype, but also had more capacity to produce IFN{gamma} than other CD161+CCR6+ Th17 cells. Additionally, in progressors, IL-17 and IL-22 production in this cell state was significantly lower than in non-progressors. Reduced abundance and function of this state may be an important factor in failure to control M.tb infection.

immunology↗