Biology subjects

Stern, L.

Publications and source records attributed to Stern, L..

6 recordsLinked to original sources

bioRxiv2026

Nectar chemistry reflects pollination strategies in alpine plant communities

Nectar is a primary floral reward, which can also deter non-specialist pollinators; yet, the role of complex nectar composition in plant-pollinator interactions and its relationship to other floral traits remain understudied, particularly in natural communities. We profiled the nectar metabolome of 43 co-occurring species in an alpine grassland to evaluate relationships among nectar chemistry, phylogeny, floral display traits and pollinator visitation. Field observations revealed a dominant bee vs fly visitation gradient. Several aggregated nectar traits tracked this gradient independently of plant phylogeny, indicating functional convergence: specifically, bee visitation was associated with higher nectar sucrose proportion, greater compound richness, and more divergent profiles of uncommon sugars. Nectar traits exhibited variable relationships to floral display traits, suggesting partial inter-trait phenotypic integration. Together, these findings indicate that detailed features of nectar composition, including phytochemical diversity, play a functional role in floral phenotypes, with previously unappreciated implications for plant-pollinator community ecology.

ecology↗

bioRxiv2026

Host community activity, but not always composition, explains viral biogeography in bulk and rhizosphere soils over a tomato growing season

The soil microbiome is key to plant health and nutrient acquisition, and viruses likely play important but largely unknown roles in these processes. To interrogate bulk and rhizosphere soil viral biogeography, we collected samples over a tomato growing season in California from an experiment testing arbuscular mycorrhizal fungi (AMF) treatment. We generated 78 viromes, 16S rRNA gene, and ITS1 amplicon datasets, and 33 rhizosphere metatranscriptomes. Of 67,038 DNA viral species genomes (vOTUs), 25% were previously identified, predominantely in agricultural systems, suggesting habitat filtering and greater viral homogeneity across agricultural compared to natural soils globally. Rhizospheres had significantly higher DNA viral richness than bulk soils, whereas no significant richness differences were observed for other biota. 60% of vOTUs were shared between compartments, compared to only 21-23% of bacterial and fungal taxa. Although bulk soil viral biogeography resembled that of prokaryotes, with significant structuring by moisture content, greater virome similarity between high-moisture bulk soils and rhizospheres suggests that conditions with high host activity selected for similar viral communities. In rhizospheres, while bacterial and fungal communities differed most over time, DNA and RNA viral communities differed most by sampling location, matching prokaryotic transcriptional patterns and further implicating host activity in viral biogeography. Similarly, AMF treatment induced changes in the prokaryotic transcriptome but, across biota, only significantly affected DNA viral communities. Overall, results indicate strong viral responses to spatiotemporally localized conditions, with viral biogeography reflecting both dispersal opportunities (high between neighboring bulk and rhizosphere soils, low across fields) and selection via local host activity.

genomics↗

bioRxiv2025

Solid tumor CAR T cells engineered with fusion proteins targeting PDL1 for localized IL-12 delivery

CAR T cell efficacy in solid tumors is limited due in part to the immunosuppressive TME. To improve anti-tumor responses, we hypothesized that enabling CAR T cells to secrete bifunctional fusion proteins consisting of a cytokine modifier (e.g., TGF{beta}trap, IL15, or IL12) combined with an immune checkpoint inhibitor (e.g., PDL1) will provide tumor localized immunomodulation to improve CAR T cell functionality. To that end, we engineered CAR T cells to secrete TGF{beta}trap, IL15, or IL12 molecules fused to PDL1 scFv, and assessed in vitro functionality and in vivo safety and efficacy in prostate and ovarian cancer models. CAR T cells engineered with PDL1-IL12 were superior in safety and efficacy compared to CAR T cells alone and to those engineered with PDL1 fused with TGF{beta}trap or IL15. Further, PDL1-IL12 engineered CAR T cells improved T cell trafficking and tumor infiltration, localized IFN{gamma} production, TME modulation, and anti-tumor responses, with reduced systemic inflammation-associated toxicities. We believe our PDL1-IL12 engineering strategy presents an opportunity to improve CAR T cell clinical efficacy and safety across multiple solid tumor types.

bioengineering↗

bioRxiv2023

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting

Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumor microenvironments. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies, which are being harnessed to improve solid tumor CAR T cell therapies. Here, we describe fully optimized CAR T cells targeting tumor-associated glycoprotein-72 (TAG72) for the treatment of solid tumors, identifying the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFN{gamma} secretion. These findings have culminated into a phase 1 trial evaluating safety, feasibility, and bioactivity of TAG72-CAR T cells for the treatment of patients with advanced ovarian cancer (NCT05225363). Preclinically, we found that CAR T cell-mediated IFN{gamma} production facilitated by IL-12 signaling was required for tumor cell killing, which was recapitulated by expressing an optimized membrane-bound IL-12 (mbIL12) molecule on CAR T cells. Critically, mbIL12 cell surface expression and downstream signaling was induced and sustained only following CAR T cell activation. CAR T cells with mbIL12 demonstrated improved antigen-dependent T cell proliferation and potent cytotoxicity in recursive tumor cell killing assays in vitro and showed robust in vivo anti-tumor efficacy in human xenograft models of ovarian cancer peritoneal metastasis. Further, locoregional administration of TAG72-CAR T cells with antigen-dependent IL-12 signaling promoted durable anti-tumor responses against both regional and systemic disease in mice and was associated with improved systemic T cell persistence. Our study features a clinically-applicable strategy to improve the overall efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting both regional and systemic disease.

cancer biology↗

bioRxiv2021

Immune Cell Profiling Reveals MAIT and Effector Memory CD4+ T Cell Recovery Link to Control of Cytomegalovirus Reactivation after Stem Cell Transplant

Human cytomegalovirus (HCMV) reactivation is a major opportunistic infection after allogeneic haematopoietic stem cell transplantation and has a complex relationship with post-transplant immune reconstitution. Here, we used mass cytometry to comprehensively define global patterns of innate and adaptive immune cell reconstitution at key phases of HCMV reactivation (before detection, initial detection, peak and near resolution) in the first 100 days post-transplant. In addition to identifying patterns of immune reconstitution in those with or without HCMV reactivation, we found mucosal-associated invariant T (MAIT) cell levels at the initial detection of HCMV DNAemia distinguished patients who subsequently developed low-level versus high-level HCMV reactivation. In addition, early recovery of effector-memory CD4+ T cells distinguished low-level and high-level reactivation. Our data describe distinct immune signatures that emerged with HCMV reactivation post-HSCT, and highlight MAIT cell levels at the initial detection of reactivation as a potential prognostic marker to guide clinical decisions regarding pre-emptive therapy.

immunology↗

bioRxiv2021

Human antibody immune responses are personalized by selective removal of MHC-II peptide epitopes

Human antibody responses are established by the generation of combinatorial sequence diversity in antibody variable domains, followed by iterative rounds of mutation and selection via T cell recognition of antigen peptides presented on MHC-II. Here, we report that MHC-II peptide epitope deletion from B cell receptors (BCRs) correlates with antibody development in vivo. Large-scale antibody sequence analysis and experimental validation of peptide binding revealed that MHC-II epitope removal from BCRs is linked to genetic signatures of T cell help, and donor-specific antibody repertoire modeling demonstrated that somatic hypermutation selectively targets the personalized MHC-II epitopes in antibody variable regions. Mining of class-switched sequences and serum proteomic data revealed that MHC-II epitope deletion is associated with antibody class switching and long-term secretion into serum. These data suggest that the MHC-II peptide epitope content of a BCR is an important determinant of antibody maturation that shapes the composition and durability of humoral immunity. HighlightsO_LIAntibody somatic hypermutation selectively removes MHC-II peptide epitopes from B cell receptors. C_LIO_LIAntibodies with lower MHC-II epitope content show evidence of greater T cell help, including class-switching. C_LIO_LIMHC-II peptide epitope removal from a BCR is linked to long-term antibody secretion in serum. C_LIO_LIMHC-II genotype provides a personalized selection pressure on human antibody development. C_LI

immunology↗