Biology subjects

Goldston, M.

Publications and source records attributed to Goldston, M..

3 recordsLinked to original sources

bioRxiv2026

Spatial proteomics reveals CD8+ T cell signatures and cellular niches associated with active HIV-1 replication in lymph nodes

Despite its effectiveness in suppressing active HIV-1 replication, antiretroviral therapy (ART) does not eliminate the persistent long-lived pool of HIV-1-infected reservoir cells, preventing the eradication of the infection. Lymphoid tissues are key anatomical sites where these reservoirs persist even in the presence of ART, but the mechanisms that are associated with viral persistence in lymphoid tissues and how tissue networks are reshaped in the setting of viral replication remain incompletely understood. Advances in tissue imaging offer a unique opportunity to characterize immune correlates of viral persistence. Here, we used a spatial proteomic method to map immune microenvironments in HIV-1-infected lymph nodes (LNs) at different stages of infection, including with or without ART. LNs from people with HIV-1 (PWH) were characterized by lower CD4+ T cell counts and higher CD8+ T cell counts in both the whole tissue and within follicles compared to people without HIV (PWOH). CD8+ T cells were more abundant in LN samples with active viral replication, defined by detection of the viral protein p24. Further characterization of p24+ LNs showed that CD8+ T cells located inside of B cell follicles exhibited higher levels of markers associated with immune activation and exhaustion, in addition to the inflammasome protein caspase-1. Using a spatial niche detection method, we found that LNs from PWH with varying levels of viral replication were differentially enriched for CD8+ T cells near antigen-presenting cells, myeloid cells, and fibroblasts. Notably, we found that p24+ cells were less enriched near CD8+ T cells but closer to follicular dendritic cells. Finally, comparing LNs from viremic and aviremic donors, where viremia was defined by detectable plasma viral load, we found low levels of activation markers in CD11c+ cells in aviremic donors, including NLRP3 inflammasome activation. Thus, using spatial proteomics to map the immune landscape in LNs, we identified novel markers characterizing immune cell subsets and tissue microenvironments that were differently enriched in PWH with varying levels of viremia, implying that HIV-1 infection confers long-term changes on the immune landscape in LN tissue. Collectively, these data provide new insights into the complex cell networks associated with viral replication at a key tissue reservoir site, which could be relevant for future HIV-1 cure strategies.

immunology↗

bioRxiv2025

The immunometabolic topography of tuberculosis granulomas governs cellular organization and bacterial control

Despite being heavily infiltrated by immune cells, tuberculosis (TB) granulomas often subvert the host response to Mycobacterium tuberculosis (Mtb) infection and support bacterial persistence. We previously discovered that human TB granulomas are enriched for immunosuppressive factors typically associated with tumor-immune evasion, raising the intriguing possibility that they promote tolerance to infection. In this study, our goal was to identify the prime drivers for establishing this tolerogenic niche and to determine if the magnitude of this response correlates with bacterial persistence. To do this, we conducted a multimodal spatial analysis of 52 granulomas from 16 non-human primates (NHP) who were infected with low dose Mtb for 9-12 weeks. Notably, each granulomas bacterial burden was individually quantified allowing us to directly ask how granuloma spatial structure and function relate to infection control. We found that a universal feature of TB granulomas was partitioning of the myeloid core into two distinct metabolic environments, one of which is hypoxic. This hypoxic environment associated with pathologic immune cell states, dysfunctional cellular organization of the granuloma, and a near-complete blockade of lymphocyte infiltration that would be required for a successful host response. The extent of these hypoxia-associated features correlated with worsened bacterial burden. We conclude that hypoxia governs immune cell state and organization within granulomas and is a potent driver of subverted immunity during TB.

immunology↗

bioRxiv2025

QUICHE reveals structural definitions of anti-tumor responses in triple negative breast cancer

While recent innovations in spatial biology have driven new insights into how tissue organization is altered in disease, interpreting these datasets in a generalized and scalable fashion remains a challenge. Computational workflows for discovering condition-specific differences in tissue organization typically rely on pairwise comparisons or unsupervised clustering. In many cases, these approaches are computationally expensive, lack statistical rigor, and are insensitive to low-prevalence cellular niches that are nevertheless highly discriminative and predictive of patient outcomes. Here, we present QUICHE - an automated, scalable, and statistically robust method that can be used to discover cellular niches differentially enriched in spatial regions, longitudinal samples, or clinical patient groups. In contrast to existing methods, QUICHE combines local niche detection with interpretable statistical modeling using graph neighborhoods to detect differentially enriched cellular niches, even at low prevalence. Using in silico models and spatial proteomic imaging of human tissues, we demonstrate that QUICHE can accurately detect condition-specific cellular niches occurring at a frequency of 0.5% in fewer than 20% of patient samples, outperforming the next best method which required a patient prevalence of 60% for detection. To validate our approach and understand how tumor structure influences recurrence risk in triple negative breast cancer (TNBC), we used QUICHE to comprehensively profile the tumor microenvironment in a multi-center, spatial proteomics cohort consisting of primary surgical resections, analyzing over 2 million cells from 314 patients across 5 medical centers. We discovered cellular niches that were consistently enriched in key regions of the tumor microenvironment, including the tumor-immune border and extracellular matrix remodeling regions, as well as niches statistically-associated with patient outcomes, including recurrence status and recurrence-free survival. The majority of differential niches (74.2%) were specific to patients that did not relapse and formed a robust interconnected network enriched in monocytes, macrophages, APCs, and CD8T cells with tumor and stroma cells. In contrast, the interaction network for patients that relapsed was notably sparse and enriched in B cells, CD68 macrophages and neutrophils. We validated these findings using two independent cohorts, observing similar cellular interactions and predictive power. Collectively, these results suggest that salient, generalized profiles of productive anti-tumor immune responses are defined by a network of structural engagement between innate and adaptive immunity with tumor and stromal cells, rather than by any single specific cell population. We have made QUICHE freely available as a user-friendly open-source Python package at https://github.com/jranek/quiche.

bioinformatics↗