Biology subjects

Chatterjee, F.

Publications and source records attributed to Chatterjee, F..

5 recordsLinked to original sources

bioRxiv2026

Radiation therapy synergizes with mRNA vaccination to overcome microglia-mediated suppression of dendritic cell migration and T cell priming in glioblastoma

Glioblastomas (GBMs) are uniformly fatal brain tumors resistant to immunotherapy, yet the mechanisms driving immune dysfunction remain poorly understood. Here we identify a tissue-specific mechanism of dendritic cell (DC) dysfunction contributing to GBM immune evasion. We demonstrate that while systemic immunity depends on type 1 conventional DCs (cDC1s), GBMs preferentially accumulate cDC2s with impaired antigen-presenting capacity. Further, microglia-derived GAS6 and PROS1 signaling through the AXL receptor on DCs suppresses DC activation and, critically, migration to tumor-draining lymph nodes. Pharmacologic AXL inhibition enhances DC migration and consequently anti-tumor immunity. Importantly, radiation therapy activates cDC1-mediated endogenous immune responses, which synergizes with mRNA vaccination to promote complete and durable immune-mediated tumor regression. These findings establish DC-mediated immunity as a therapeutic target in brain tumors and reveal a synergistic mechanism for combining radiation with personalized cancer vaccines.

cancer biology↗

bioRxiv2026

Lymph node resident memory T cells retain effector capabilities by evading lung resident memory dysfunction.

Resident memory T cells (TRM) mediate localized immunity in barrier tissues while central memory T cells (TCM) recirculate through lymphoid organs to surveil for reinfection. Although TRM are classically associated with peripheral non-lymphoid tissues, they have also been identified within lymph nodes (LNRM) where the mechanisms guiding their formation and functional differences remain poorly understood. Here we used longitudinal antibody labeling to track the migratory history of memory T cells after influenza infection and demonstrate that CD69+CD103+ T cells are resident in the lymph node. LNRM accumulate evenly throughout the lung-draining lymph node and are present within all analyzed LN compartments including, the sub capsular sinus, T cell zone and germinal centers. Epigenetic and transcriptional profiling reveal that LNRM are uniquely poised for cytotoxicity whereas TRM in the lung (LungRM) resemble exhausted cells with elevated expression of inhibitory receptors and increased chromatin accessibility at the Pdcd1 locus. Regulatory network analysis of transcription factors, combined with target gene expression and chromatin accessibility, identified key regulons differentiating TCM, LNRM and LungRM states. Upon antigen re-encounter, LNRM are more proliferative, cytotoxic, and produce more IFN{gamma} compared to LungRM. Notably, we find that LNRM represent the most prevalent subset of memory T cells in human thoracic lymph nodes. These findings highlight functional heterogeneity in TRM and establish LNRM as a distinct and durable memory T cell population bridging features of circulating and tissue-resident cells.

immunology↗

bioRxiv2025

PD-1 blockade during T cell priming enhances long-term protection against metastatic tumors by epigenetically tuning T cell exhaustion

In cancer, CD8+ T cell responses are dominated by exhausted T cells, which can be reinvigorated using immune checkpoint blockade therapy and can control large tumors. However, it remains unclear which T cell fate best supports long-term immunity following tumor regression or clearance and a period of minimal antigen load. This question is particularly relevant following surgical tumor resection, when tuning the immune system could prevent recurrence. To determine which T cell fate provides durable protection following surgery and metastatic rechallenge, we modulated T cell priming using anti-PD-1, IFN-{beta} or agonistic anti-CD40 and assessed effects on CD8+ T cell differentiation and overall survival. IFN-{beta} and anti-CD40 promoted effector and memory-like T cell states, respectively, whereas anti-PD-1 did not markedly alter T cell differentiation, yet conferred the greatest survival benefit against metastatic tumors. Notably, anti-PD-1 induced epigenetic remodeling, which was detectable upon metastatic recall, consistent with the maintenance of a circulatory intermediate-exhausted T cell state. Thus, while effector and memory precursor-like T cells could be generated with IFN-{beta} and agonistic anti-CD40, only the intermediate-exhausted T cell state driven by anti-PD-1 supported durable anti-tumor immunity. SummaryThis study shows that PD-1 blockade during T cell priming promotes a circulatory intermediate-exhausted CD8 T cell state that uniquely supports durable anti-tumor immunity after surgical resection and metastatic challenge, outperforming effector or memory-like T cell responses generated by IFN-{beta} or CD40 agonist treatment, respectively.

immunology↗

bioRxiv2022

A model for Scc2p Stimulation of Cohesin's ATPase and its Inhibition by Acetylation of Smc3p

The evolutionarily conserved cohesin complex mediates sister chromatid cohesion and facilitates mitotic chromosome condensation, DNA repair, and transcription regulation. These biological functions require cohesins two ATPases, formed by the Smc1p and Smc3p subunits. Cohesins ATPase activity is stimulated by the Scc2p auxiliary factor. This stimulation is inhibited by Eco1p acetylation of Smc3p at an interface with Scc2p. It was unclear how cohesins ATPase activity is stimulated by Scc2p, or how acetylation inhibits Scc2p, given that the acetylation site is distal to cohesins ATPase active sites. Here, we identify mutations in budding yeast that suppressed the in vivo defects caused by Smc3p acetyl-mimic and acetyl-defective mutations. We provide compelling evidence that Scc2p activation of cohesin ATPase depends upon an interface between Scc2p and a region of Smc1p proximal to cohesins Smc3p ATPase active site. Furthermore, substitutions at this interface increase or decrease ATPase activity to overcome ATPase modulation by acetyl-mimic and - null mutations. Using these observations and a cryo-EM structure, we propose a model for regulating cohesin ATPase activity. We suggest that Scc2p binding to Smc1p causes a shift in adjacent Smc1p residues and ATP, stimulating the Smc3p ATPase. This stimulatory shift is inhibited through acetylation of the distal Scc2p-Smc3 interface.

genetics↗

bioRxiv2019

Communication between distinct subunit interfaces of the cohesin complex promotes its topological entrapment of DNA.

Cohesin mediates higher-order chromosome structure. Its biological activities require topological entrapment of DNA within a lumen(s) formed by cohesin subunits. The reversible dissociation of cohesins Smc3p and Mcd1p subunits are postulated to form a regulated gate that allows DNA entry and exit into the lumen. We assessed gate-independent functions of this interface in yeast using a fusion protein that joins Smc3p to Mcd1p. We show that in vivo all the regulators of cohesin promote DNA binding of cohesion by mechanisms independent of opening this gate. Furthermore, we show that this interface has a gate-independent activity essential for cohesin to bind chromosomes. We propose this interface regulates DNA entrapment by controlling the opening and closing of one or more distal interfaces formed by cohesin subunits, likely by inducing a conformation change in cohesin. Furthermore, cohesin regulators modulate the interface to control both DNA entrapment and cohesin functions after DNA binding.

genetics↗