An estimated 32 million people live with HIV-1 globally. Combined antiretroviral therapy suppresses viral replication but therapy interruption results in viral rebound from a latent reservoir mainly found in memory CD4+ T cells. Treatment is therefore lifelong and not curative. Eradication of this viral reservoir requires hematopoietic stem cell transplantation from hemizygous or homozygous ΔCCR5 donors, which is not broadly applicable. Alternative cure strategies include the pharmacological reactivation of latently infected cells to promote their immune-mediated clearance, or the induction of deep latency. HIV-1 latency is multifactorial and linked to the activation status of the infected CD4+ T cell. Hence to perturb latency, multiple pathways need to be simultaneously targeted without affecting CD4+ T cell function. Hsp90 has been shown to regulate HIV-1 latency, although knowledge on the pathways is limited. Because Hsp90 promotes the proper folding of numerous cellular proteins required for HIV-1 gene expression, we hypothesized that Hsp90 might be a master regulator of latency. We tested this hypothesis using a polyclonal Jurkat cell model of latency and ex-vivo latently infected primary CD4+ T cells. We found that, in the Jurkat model, Hsp90 is required for HIV-1 reactivation mediated by the T-cell receptor, phorbol esters, TNF-α, inhibition of FOXO-1, and agonists of TLR-7 and TLR-8. In primary cells, Hsp90 regulates HIV-1 gene expression induced by stimulation of the T-cell receptor or in the presence of IL-7/IL-15 or a FOXO-1 inhibitor. Chemical inhibition of Hsp90 abrogated activation of the NF-kB, NFAT and AP-1 signal transduction pathways. Within the CD4+ T cell population, CDRA45+ CCR7+ "naïve" and CD45RA- CCR7- "effector memory" cells were most sensitive to Hsp90 inhibition, which did not perturb their phenotype or activation state. Our results indicate that Hsp90 is a master regulator of HIV-1 latency that can potentially be targeted in cure strategies.
Copyright: © 2025 Noorsaeed et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Neurotransmitters are key modulators in neuro-immune circuits and have been linked to tumor progression. Medullary thyroid cancer (MTC), an aggressive neuroendocrine tumor, expresses neurotransmitter calcitonin gene-related peptide (CGRP), is insensitive to chemo- and radiotherapies, and the effectiveness of immunotherapies remains unknown. Thus, a comprehensive analysis of the tumor microenvironment would facilitate effective therapies and provide evidence on CGRP's function outside the nervous system. Here, we compare the single-cell landscape of MTC and papillary thyroid cancer (PTC) and find that expression of CGRP in MTC is associated with dendritic cell (DC) abnormal development characterized by activation of cAMP related pathways and high levels of Kruppel Like Factor 2 (KLF2), correlated with an impaired activity of tumor infiltrating T cells. A CGRP receptor antagonist could offset CGRP detrimental impact on DC development in vitro. Our study provides insights of the MTC immunosuppressive microenvironment, and proposes CGRP receptor as a potential therapeutic target.
© 2024. The Author(s).

Systemic Lupus Erythematosus (SLE) is a progressive disease leading to immune-mediated tissue damage, associated with an alteration of lymphoid organs. Therapeutic strategies involving regulatory T (Treg) lymphocytes, which physiologically quench autoimmunity and support long-term immune tolerance, are considered, as conventional treatment often fails. We describe here a therapeutic strategy based on Tregs overexpressing FoxP3 and harboring anti-CD19 CAR (Fox19CAR-Tregs). Fox19CAR-Tregs efficiently suppress proliferation and activity of B cells in vitro, which are relevant for SLE pathogenesis. In an humanized mouse model of SLE, a single infusion of Fox19CAR-Tregs restricts autoantibody generation, delay lymphopenia (a key feature of SLE) and restore the human immune system composition in lymphoid organs, without detectable toxicity. Although a short survival, SLE target organs appear to be protected. In summary, Fox19CAR-Tregs can break the vicious cycle leading to autoimmunity and persistent tissue damage, representing an efficacious and safe strategy allowing restoration of homeostasis in SLE.
© 2024. The Author(s).

Revealing the single-cell immune ecosystems in true versus de novo hepatocellular carcinoma (HCC) recurrences could help the optimal development of immunotherapies.
We performed 5'and VDJ single-cell RNA-sequencing on 34 samples from 20 recurrent HCC patients. Bulk RNA-sequencing, flow cytometry, multiplexed immunofluorescence, and in vitro functional analyses were performed on samples from two validation cohorts.
Analyses of mutational profiles and evolutionary trajectories in paired primary and recurrent HCC samples using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The tumour immune microenvironment (TIME) of truly recurrent HCCs was characterised by an increased abundance in KLRB1+CD8+ T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8+ T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed elevated GDF15 expression on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited antitumour immunity in truly recurrent lesions. In contrast, myeloid cells' cross talk with T cells-mediated T cell exhaustion and immunosuppression in the TIME of de novo recurrent HCCs. Consistent with these findings, a phase 2 trial of neoadjuvant anti-PD-1 immunotherapy showed more responses in de novo recurrent HCC patients.
True and de novo HCC recurrences occur early, have distinct TIME and may require different immunotherapy strategies. Our study provides a source for genomic diagnosis and immune profiling for guiding immunotherapy based on the type of HCC recurrence and the specific TIME.
© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.

Erythroblastic islands (EBIs) are the specialized structures for erythropoiesis, but they have never been found functional in tumors. As the most common pediatric liver malignancy, hepatoblastoma (HB) requires more effective and safer therapies to prevent progression and the lifelong impact of complications on young children. However, developing such therapies is impeded by a lack of comprehensive understanding of the tumor microenvironment. By single-cell RNA sequencing of 13 treatment-naive HB patients, we discover an immune landscape characterized by aberrant accumulation of EBIs, formed by VCAM1+ macrophages and erythroid cells, which is inversely correlated with survival of HB. Erythroid cells inhibit the function of dendritic cells (DCs) via the LGALS9/TIM3 axis, leading to impaired anti-tumor T cell immune responses. Encouragingly, TIM3 blockades relieve the inhibitory effect of erythroid cells on DCs. Our study provides an immune evasion mechanism mediated by intratumoral EBIs and proposes TIM3 as a promising therapeutic target for HB.
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.