Biology subjects

Nghiem, P.

Publications and source records attributed to Nghiem, P..

6 recordsLinked to original sources

bioRxiv2025

B cells specific for polyomavirus-derived oncoprotein are predictive of Merkel cell carcinoma progression

Merkel cell carcinomas typically arise from clonal integration of the Merkel cell polyomavirus. Immunogenic viral oncoproteins then lead to tumorigenesis. Oncoprotein-specific T cells are essential for anti-MCC immunity, but it is unclear whether B cells promote tumor control. Here, we analyzed the frequency and phenotype of viral oncoprotein-specific and total B cells in 47 blood samples and 19 unmatched tumors from MCC patients-- of which 8 out 19 progressed. The phenotype of blood B cells did not correlate with MCC patient outcomes. In contrast, all 11 patients with robust oncoprotein-specific antibody-secreting and/or germinal center B cells in tumors experienced long-term MCC control. In vitro, B cells engineered to be specific for viral oncoproteins increased the sensitivity of oncoprotein-specific CD4+ T cells by over 50-fold. Together, our findings suggest that cancer-specific B cells promote anti-tumor immunity via increased T cell responses and that cancer-specific B cell augmentation could be therapeutically relevant. Statement of SignificanceThe link between cancer-specific B cells in anti-tumor immunity and clinical outcomes remains poorly defined. Here, we show that tumor-associated B cells specific for a viral oncoprotein expressed in MCC patient tumors predict disease control with remarkable accuracy, establishing their potential as active participants in tumor immunity.

immunology↗

bioRxiv2024

Merkel cell carcinoma-derived macrophage migration inhibitory factor (MIF) may promote persistence of Chronic Lymphocytic Leukemia

While concurrent diagnoses of Merkel cell carcinoma (MCC) and other cancers, like Chronic lymphocytic leukemia (CLL), are rare, patients with MCC have a 30-fold higher incidence of CLL. While these increases have been attributed to the ability of CLL to suppress immune responses allowing for the emergence of MCC, here we found evidence that MCC could support the persistence of CLL. Using single cell sequencing approaches and computational analyses of MCC and CLL from a patient where both cancers were present in the same lymph node, we found that production of macrophage migration inhibitory factor (MIF) by MCC could promote the persistence of CLL through stimulation of CD74 and CXCR4. These results may explain why blood cell counts rapidly normalized after treatment for MCC and were maintained at normal levels despite the absence of treatment for CLL. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/611517v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@188968forg.highwire.dtl.DTLVardef@54c084org.highwire.dtl.DTLVardef@2b3a14org.highwire.dtl.DTLVardef@1f20eba_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Tempered IL-2 Signals Program PD-1 Checkpoint Blockade-Responsive Stem-like Exhausted T Cells During Priming

Stem-like progenitor exhausted CD8 T cells are critical for maintaining long-term resistance during chronic infections and cancer, and represent an important checkpoint blockade immunotherapy target for functional reinvigoration and disease control. Hence, there is vigorous interest in understanding the ontogenesis of TCF-1Hi stem-like exhausted CD8 T cells, and in defining the signals that promote their development. Here, we show that virus-specific TCF1HiGzmBLo CD8 T cells develop during early stages of chronic viral infection, and are progressively deprogrammed from the stem-like lineage towards terminal differentiation by strong IL-2 signals. In vivo fate-tracking studies show that strong T cell-intrinsic IL-2 signals through the high affinity heterotrimeric IL-2R/{beta}/{gamma} receptor drive skewed development of terminally differentiated TCF-1LoGzmBHi cells, which largely die in chronic antigenic environment. In contrast, tempered IL-2 signals through the intermediate affinity IL-2R{beta}/{gamma} heterodimer, or delayed priming in diminished IL-2 milieu support preferential development of TCF-1Hi stem-like exhausted CD8 T cells, capable of long-term persistence and potent responsiveness to PD-1 therapy in later stages of chronic viral infection. In human tumors as well, single cell RNA-seq analyses of tumor infiltrating lymphocytes from melanoma, human papillomavirus+ head and neck cancer and lung cancer patients revealed an inverse relationship between IL-2 signaling signature and T cell stemness. Moreover, melanoma patients with enriched IL-2 signaling signature showed poor responses to checkpoint blockade immunotherapy. Collectively, these findings bear relevance to clinical immunotherapies of chronic viral infections and cancers, and support exogenous IL-2 signal manipulation prior to therapy as a strategy for augmenting long-term clinical outcomes. ONE SENTENCE SUMMARYProgramming of exhausted T cell fates by differential IL-2

immunology↗

bioRxiv2022

Interferon-gamma Elicits Pathological Hallmarks of ALS in Human Motor Neurons

Neuroinflammation is an established factor contributing to amyotrophic lateral sclerosis (ALS) pathology, implicating the possible detrimental effects of inflammatory cytokines on motor neurons. The RNA/DNA-binding protein TDP-43 has emerged as a pivotal actor in ALS, because TDP-43 mutations cause familial ALS and loss of nuclear TDP-43, associated with its redistribution into cytoplasmic aggregates (TDP-43 proteinopathy) in motor neurons occurs in 97% of ALS cases. However, mechanisms linking neuroinflammation to TDP-43 mislocalization have not been described. Programmed death-ligand 1 (PD-L1) is an immune-modulatory protein, highly expressed on cell surfaces following acute inflammatory stress. To determine which inflammatory cytokines might impact motor neuron function, seven cytokines known to be elevated in ALS patients cerebrospinal fluid were tested for their effects on PD-L1 expression in human iPSC-derived motor neurons. Among the tested cytokines, only interferon-{gamma} (IFN-{gamma}) was found to strongly promote PD-L1 expression. Thus, we hypothesized that excessive exposure to IFN-{gamma} may contribute to motor neuron degeneration in ALS. We observed that neuronal populations exposed to IFN-{gamma} exhibited severe TDP-43 cytoplasmic aggregation and excitotoxic behavior correlated with impaired neural firing activity, hallmarks of ALS pathology, in both normal and ALS mutant (TARDB1K+/-) neurons. Single-cell RNA sequencing revealed possible mechanisms for these effects. Motor neurons exposed to IFN-{gamma} exhibited an extensive shift of their gene expression profile toward a neurodegenerative phenotype. Notably, IFN-{gamma} treatment induced aberrant expression levels for 70 genes that are listed in the recent literature as being dysregulated in various ALS subtypes. Additionally, we found that genes related to neuronal electrophysiology, protein aggregation, and TDP-43 misregulation were abnormally expressed in IFN-{gamma} treated cells. Moreover, IFN-{gamma} induced a significant reduction in the expression of genes that encode indispensable proteins for neuromuscular synapse development and maintenance, implying that the continuous cytokine exposure could directly impair signal transmission between motor axons and muscle membranes. Our findings suggest that IFN-{gamma} could be a potent upstream pathogenic driver of ALS and provide potential candidates for future therapeutic targets to treat sporadic forms of ALS, which account for roughly 90% of reported cases.

neuroscience↗

bioRxiv2021

Differential effects of high versus low linear energy transfer (LET) radiation on type-I interferon (IFNβ) and TREX1 responses

PurposeCancer cells produce innate immune signals following radiation damage, with STING pathway signaling as a critical mediator. High linear energy transfer (LET) radiations create larger numbers of DNA double-strand breaks (DSBs) per unit dose than low-LET radiations and may therefore be more immunogenic. We studied the dose response characteristics of pro-immunogenic type-I interferon, interferon-beta (IFN{beta}), and its reported suppressor signal, three-prime repair exonuclease 1 (TREX1), in vitro with low-LET x-rays and high-LET fast neutrons. MethodsMerkel cell carcinoma cells (MCC) were irradiated by graded doses of x-rays (1-24 Gy) or fast neutrons (1-8 Gy). IFN{beta} was measured as a function of dose via ELISA assay, and exonuclease TREX1 expression via immunofluorescence microscopy. The Monte Carlo damage simulation (MCDS) was used to model fast neutron relative biological effectiveness for DSB induction (RBEDSB) and compared to laboratory measurements of the RBE for IFN{beta} production (RBEIFN{beta}) and TREX1 upregulation (RBETREX1). RBEIFN{beta} models were also applied to radiation transport simulations to quantify the potential secretion of IFN{beta} in representative clinical beams. ResultsPeak IFN{beta} secretion occurred at 5.7 Gy for fast neutrons and at 14.0 Gy for x-rays, i.e., an effective RBEIFN{beta} of 2.5 {+/-} 0.2. The amplitude (peak value) of secreted IFN{beta} signal did not significantly differ between x-rays and fast neutrons (P > 0.05). TREX1 signal increased linearly with absorbed dose, with a four-fold higher upregulation per unit dose for fast neutrons relative to x-rays (RBETREX1 of 4.0 {+/-} 0.1). Monte Carlo modeling of IFN{beta} suggests Bragg peak-to-entrance ratios of IFN{beta} production of 40, 100, and 120 for proton, alpha, and carbon ion beams, respectively, a factor of 10-20-fold higher compared to their corresponding physical dose peak-to-entrance ratios. The spatial width of the Bragg peak for IFN{beta} production is also a factor of two smaller. ConclusionHigh-LET fast neutrons initiate a larger IFN{beta} response per unit absorbed dose than low-LET x-rays (i.e., RBEIFN{beta} value of 2.5). The RBE value for IFN{beta} is quite similar to data reported in the literature for DSB induction and cellular, post-irradiation micronucleation formation for neutrons and x-rays. The increased IFN{beta} release after high-LET radiation may be a contributing factor in stimulating a systemic anti-tumor, adaptive immune response (abscopal effect). However, our results indicate that TREX1 anti-inflammatory signaling in vitro for MCC cells is larger per unit dose for fast neutrons than for x-rays (RBETREX1 of 4.0). Given these competing effects, additional studies are needed to clarify whether or not high-LET radiations are therapeutically advantageous over low-LET radiation for pro-inflammatory immune signaling in other cell lines in vitro and for in vivo cancer models.

cancer biology↗

bioRxiv2020

BayesSpace enables the robust characterization of spatial gene expression architecture in tissue sections at increased resolution

Recently developed spatial gene expression technologies such as the Spatial Transcriptomics and Visium platforms allow for comprehensive measurement of transcriptomic profiles while retaining spatial context. However, existing methods for analyzing spatial gene expression data often do not efficiently leverage the spatial information and fail to address the limited resolution of the technology. Here, we introduce BayesSpace, a fully Bayesian statistical method for clustering analysis and resolution enhancement of spatial transcriptomics data that seamlessly integrates into current transcriptomics analysis workflows. We show that BayesSpace improves the identification of transcriptionally distinct tissues from spatial transcriptomics samples of the brain, of melanoma, and of squamous cell carcinoma. In particular, BayesSpaces improved resolution allows the identification of tissue structure that is not detectable at the original resolution and thus not recovered by other methods. Using an in silico dataset constructed from scRNA-seq, we demonstrate that BayesSpace can spatially resolve expression patterns to near single-cell resolution without the need for external single-cell sequencing data. In all, our results illustrate the utility BayesSpace has in facilitating the discovery of biological insights from a variety of spatial transcriptomics datasets.

bioinformatics↗