Immunology
Abstract
Primary and metastatic brain tumors exhibit resistance to immunotherapies that demonstrate efficacy in peripheral cancer settings. While many immunotherapies aim to enhance CD8+ T cell infiltration and functionality in established tumors, identification of neoantigens support emerging immunopreventative tactics against brain cancer. Functionally potent tissue-resident memory CD8+ T cells (TRM) can be generated in the brain following peripheral infection or vaccination. However, the ability of brain TRM to prevent intracranial malignancy remains unknown. Here, mice were seeded with tumor-specific or bystander brain TRM via peripheral infection prior to depletion of circulating memory T cells (TCIRCM) and subsequent brain tumor challenge. Tumor-specific brain TRM durably protected mice against intracranial malignancy even in the absence TCIRCM. These brain TRM persisted in tumor-surviving mice and protected against a second antigen-matched challenge. Importantly, a translationally-relevant mRNA-lipid nanoparticle (LNP) vaccine phenocopied peripheral infection-induced outcomes, generating functional brain TRM that controlled tumor growth. Altogether, this work points to the utility of brain TRM in cancer immunoprevention, supporting the development of antitumor mRNA-LNP vaccines to bolster brain immunity.
Authors
Madison R. Mix, Cassie M. Sievers, Mariah Hassert, Shravan Kumar Kannan, Lecia L. Pewe, Sunny C. Huang, Rui He, Cori E. Fain, Mohammad Heidarian, Lisa S. Hancox, Sahaana A. Arumugam, Terry G. Beltz, Fang Jin, Aaron J. Johnson, Calvin S. Carter, Noah S. Butler, Aliasger K. Salem, Vladimir P. Badovinac, John T. Harty
Abstract
Authors
Lawrence W. Rasmussen, Deepali Luthra, Diego Moncada-Giraldo, Crystal Lewis, Yixel M. Soto-Vazquez, Zhuo Li, Buqu Hu, Brian S. Dobosh, Delores A. Stacks, Jonathan L. Koff, Amit Gaggar, Rabindra Tirouvanziam, Camilla Margaroli
Abstract
Background. Functional B cell responses for both prevention and control of hepatitis B virus (HBV) infection remain poorly understood, including in the context of HBV/HIV co-infection. Methods. Here, we employed high-dimensional single cell analysis to assess global and hepatitis B surface antigen (HBsAg)-specific B cells in a longitudinal cohort of incident HBV from the Multicenter Aids Cohort Study (MACS), with a subset of the cohort living with HIV-1. Results. We observed that prior HIV infection has negative consequences for B cell function in early post-acute HBV infection, including increased frequencies of atypical memory (AtM) B cells and regulatory B cells (Bregs), expression of the activation marker CD86 on multiple B cell subsets in chronic HBV (CHB), and restricted expansion of HBsAg-specific B cells. In contrast, in HBV mono-infection, we observed no changes in the global B cell population from prior to infection and robust expansion of HBsAg-specific B cells. These expanded antigen-specific B cells resembled class-switched intermediate and resting memory (IM and RM) B cells, with activation phenotypes that may contribute to ongoing HBV control. Conclusion. HIV infection has a significant impact on B cell responses to subsequent HBV infection that may promote development of CHB in HBV/HIV co-infection. Funding. National Institute of Allergy and Infectious Diseases, Bill & Melinda Gates Foundation.
Authors
Katherine Cascino, Thomas Liechti, Eric C. Seaberg, Kathleen E. Stevens, Steven M. Wolinsky, Mallory D. Witt, Robbie B. Mailliard, Mario Roederer, Justin Bailey, Chloe L. Thio, Andrea L. Cox
Abstract
Immunotherapies achieve durable responses in several cancers but show limited efficacy in refractory hepatocellular carcinoma (HCC). The mechanisms by which hepatoma cells evade immune recognition and limit immune checkpoint blockade (ICB) efficacy are incompletely defined. Here, we identified tumor-intrinsic tescalcin (TESC) as a previously unrecognized phagocytic checkpoint that contributes to immune evasion and ICB resistance in HCC. Mechanistically, H3K4 methylation drove TESC expression in hepatoma cells, facilitating cytosolic Ca²⁺ buffering and attenuating endoplasmic reticulum (ER) stress-induced calreticulin (CALR) plasma membrane exposure, an essential “eat-me” signal. Consequently, this process abrogates membrane CALR-directed phagocytosis by antigen-presenting cells (APCs), including macrophages and dendritic cells, thereby impairing antigen presentation and subsequent T-cell activation. Clinically, elevated H3K4me3-TESC signaling was a promising prognostic biomarker for poor ICB response of HCC. Importantly, in vivo disruption of this axis restored APC phagocytic function and enhanced the antitumor effects of ICB therapy. Thus, targeting TESC-driven immune escape and its underlying epigenetic regulation may restore APC function and offer a precise therapeutic strategy to enhance immunotherapy efficacy in HCC.
Authors
Jiong-Liang Wang, Jun-Cheng Wang, Yangxun Pan, Minrui He, Zhikai Zheng, Hao Zou, Tianqing Wu, Yuhan Zhang, Zili Hu, Yizhen Fu, Wei Peng, Zhenyun Yang, Li Xu, Yao-Jun Zhang, Min-Shan Chen, Dandan Hu, Jinbin Chen, Ming Zhao, Dong-Ping Chen, Zhong-Guo Zhou
Abstract
Traumatic brain injury (TBI) disproportionately affects the elderly, yet the underlying mechanisms remain unclear. Here, we demonstrate that aged TBI brains predominantly harbor pro-inflammatory NLRP3+ microglia, in stark contrast to the neuroprotective Lysozyme+ microglia prevalent in young TBI brains. This age-dependent microglial dichotomy correlates with elevated mortality and impaired recovery in aged TBI mice. By leveraging an integrative multi-omics approach combined with metabolomics and epigenome analysis, we identify a previously unrecognized link between enhanced glycolysis and pro-inflammatory chromatin landscape in NLRP3+ microglia. Further investigation identifies ELF1 as a key transcription factor driving NLRP3+ microglia formation. Importantly, ablation of ELF1 reverses age-associated microglial dysfunction and improves TBI outcomes. Finally, we discover that Imeglimin, a clinically approved antihyperglycemic agent capable of crossing the blood brain barrier, inhibits ELF1 and reverses microglial phenotype, reducing acute mortality rate and leading to improved functional recovery of aged TBI mice. Our work elucidates the mechanistic basis of age-dependent TBI outcomes, reveals the crosstalk between metabolic rewiring and epigenetic regulation in microglial aging, and identifies ELF1 as a promising therapeutic target for improving TBI outcome.
Authors
Zhichao Lu, Yi Shuai, Chenxing Wang, Zongheng Liu, Ziheng Wang, Qianqian Liu, Rui Jiang, Jue Zhu, Yongqi Zhu, Weiquan Liao, Xingjia Zhu, Jingwei Zhao, Kaibin Shi, Wei Shi, Peipei Gong
Abstract
Early initiation of antiretroviral therapy (ART) in perinatally HIV-infected children significantly limits the establishment of the viral reservoir. However, the long-term impact of this intervention remains unclear. We measured the frequency of inducible, translation-competent, and replication-competent proviruses in samples from 62 children who initiated ART early (median 9.9 weeks) and remained virally suppressed for up to 9.9 years. Only a small fraction of HIV genomes produced HIV transcripts (1.8%), viral proteins (<0.9%) or infectious virions (<0.05%). Accordingly, replication-competent virus was detected in only 15% of the participants. Despite the predominance of naïve cells in pediatric blood, most proviruses were detected in memory CD4+ T cells, especially central memory cells (contribution 41%). Longitudinal analysis revealed a biphasic decay in HIV DNA: an initial decline followed by long-term stability, which was associated with extensive expansions of infected T-cell clones. In contrast, inducible proviruses declined continuously and became undetectable in most children after five years. Near full-length sequencing of 1,305 HIV genomes revealed a dramatic reduction in genetically intact proviruses, from 40% pre-ART to 0.3% after 7 years of ART. Together, these findings suggest that the intact viral reservoir rapidly decays in early-treated children, offering critical insights for pediatric HIV cure strategies.
Authors
Marta Massanella, Caroline Dufour, Amélie Pagliuzza, Audrée Lemieux, Corentin Richard, Jintanat Ananworanich, Louise Leyre, Thidarat Jupimai, Supranee Buranapraditkun, Rapisa Nantanee, Julie L. Mitchell, Panadda Sawangsinth, Mark de Souza, Piyarat Suntarattiwong, Suparat Kanjanavanit, Pope Kosalaraksa, Thitiporn Borkird, Witaya Petdachai, Kulkanya Chokephaibulkit, Lydie Trautmann, Rémi Fromentin, Thanyawee Puthanakit, Nicolas Chomont
Abstract
Epigenetic dysregulation is associated with immune evasion and immune checkpoint blockade (ICB) resistance. Here, using in vivo CRISPR-Cas9 screens targeting epigenetic-related factors in mouse tumor models treated with ICB, we identified Chromobox 4 (CBX4) as a key negative regulator of immune tumor microenvironment. Single-cell RNA sequencing and spatial transcriptomics analyses of patients receiving neoadjuvant anti-PD-1 therapy revealed high CBX4 expression in both tumor cells and immunosuppressive tumor-associated macrophage subpopulations, with preferential accumulation in non-responders. Deficiency of CBX4 in macrophages or tumor cells, induced robust anti-tumor immunity, increased infiltration and cytotoxic activity of CD8+ T cells and NK cells, thereby heightening the sensitivity of ICB treatment. Mechanistically, CBX4 targeted H3K9me3 and H3K27me3-marked endogenous retroelements such as RLTR4-Mm-int. Loss of CBX4 derepressed retrotransposons, activating cytosolic RNA-sensing pathways and triggering type I interferon response, ultimately leading to robust inflamed TME. Moreover, we uncovered a negative correlation between CBX4 expression and immune responses, retrotransposon levels as well as the prognosis of patients with hepatocellular carcinoma (HCC) undergoing ICB therapy. Our study establishes CBX4 as an epigenetic immune checkpoint through the epigenetic silencing of retrotransposons, remodeling immune TME and thus providing a promising therapeutic target to enhance tumor immunogenicity and overcoming immunotherapy resistance.
Authors
Zhibo Ma, Wenlong Jia, Xi Zhou, Jing Liu, Qingwen Li, Ruizhi Chang, Shiqi Gu, Naonao Yuan, Zhishui Chen, Peixiang Lan
Abstract
The peritoneal cavity contains a large population of GATA6-expressing large peritoneal macrophages (LPMs), known to support healing of intra-abdominal organs. In this study, we aimed to explore their full sphere of influence by examining their ability to perform wound healing at distant sites outside the cavity. In a mouse model combining a remote skin injury with peritoneal stimulation we observed a significant acceleration of skin wound healing in response to LPM activation. Tracking GATA6-expressing LPMs, we demonstrated that LPMs do not migrate to distant wound sites following peritoneal activation. Using parabiosis experiments and administration of activated peritoneal contents indicated an important role of molecules secreted by LPMs in remote skin wound healing. More specifically, proteomic and transcriptomic analyses identified fibronectin as a key factor produced by activated LPMs. In fact, depletion of LPMs or genetic knockout of fibronectin in myeloid cells eliminated the enhanced healing effect. These findings highlight the endocrine function of LPMs in systemic tissue repair, challenging the traditional perspective of plasma fibronectin being exclusively liver-derived. Our results suggest that LPMs, strategically positioned in the peritoneal cavity, serve as a source of circulating fibronectin, promoting matrix formation and accelerating wound healing at distant sites.
Authors
Lilian Salm, Simone N. Zwicky, Daniel Spari, Tural Yarahmadov, Marie Siwicki, Fernanda VS Castanheira, Jonas Zbinden, Deborah Stroka, Joel Zindel, Antoine Dufour, Paul Kubes, Guido Beldi
Abstract
Single-agent anti-PD-1 antibody is ineffective for pancreatic ductal adenocarcinoma (PDAC) due to its immunosuppressive tumor-microenvironment (TME). KRAS-mutations contribute to the inflammatory TME and therapeutic resistance by upregulating IL-8 via MAPK pathways. Thus, this study attempted to overcome the resistance to anti-PD-1 antibody by targeting downstream KRAS-effectors. The study found that the resistance to anti-PD-1 antibody can be overcome through MEK1/2-inhibition. The combination of anti-PD-1 antibody and MEK inhibitor displayed antitumor activity in Krasmut (mutated) KPC mouse tumors, but not KrasWT (wild-type) Panc02 tumors. The combination of anti-PD-1 antibody and MEK inhibitor induced recruitment of tumor-associated neutrophils (TANs) via CXCR2, an IL-8 receptor, and increased memory CD8+ T cells and IFNgamma production in treatment-sensitive tumors. However, larger tumors still resisted to the combination of anti-PD-1 antibody and MEK inhibitor likely due to hypoxia/necrosis-induced NETosis and associated paucity of CD8+ T cells. The subsequent addition of anti-CXCR2 antibody overcame this resistance by blocking TAN-infiltration to hypoxic/necrotic areas. Consistently, a risk-score based on the NETosis-MAPK signaling interaction is significantly associated with poorer survival in human PDACs. This study thus provides a new venue for overcoming resistance to strategies targeting KRAS signaling.
Authors
Brian Herbst, Alex B. Blair, Yiming Li, Elizabeth M. Jaffee, Lei Zheng
Abstract
Glioblastoma (GBM) is a highly aggressive brain tumor characterized by extensive crosstalk between glioblastoma stem cells (GSCs) and immunosuppressive microglia, with our previous work identifying CLOCK and TFPI2 as key regulators of this interaction. Here, we uncover a ‘symbiotic exclusivity’ pattern between CLOCK and TFPI2, showing that despite mutually exclusive amplifications, they sustain symbiotic regulatory interactions in GBM. The CLOCK-BMAL1 complex transcriptionally upregulates TFPI2, while TFPI2-driven hypoxia inducible factor 1 alpha (HIF1a) signaling activates nuclear factor kappa B (NF-kB) P65 to upregulate the CLOCK-BMAL1 complex, creating a positive feedback loop to promote stemness, immunosuppression, and tumor progression. Disrupting the CLOCK-TFPI2 interplay through dual inhibition of their downstream effectors reduces GSC stemness and immunosuppressive microglia, activates antitumor immunity, and synergizes with anti-PD1 therapy to achieve complete tumor regression in 50-62.5% of tumor-bearing mice. This study uncovers a promising therapeutic strategy for a broader subset of GBM patients with high expression of either CLOCK or TFPI2, and provides a framework for identifying 'symbiotic exclusivity' genes in cancer.
Authors
Fei Zhou, Lizhi Pang, Yang Liu, Fatima Khan, Peiwen Chen
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)