Biology subjects

Alban, T.

Publications and source records attributed to Alban, T..

8 recordsLinked to original sources

bioRxiv2026

Engineering Endogenous T Cell Receptors to Recognize Cancer Neoantigens Using a Hybrid Physics-AI Approach

T cell receptors (TCRs) are critical for immune surveillance and successful adaptive immune response against foreign antigens. TCRs drive this key arm of the immune system through recognition of peptide epitopes presented on MHC complexes. However, they are limited due to their stochastic nature and generation via genetic recombination. In silico design of functional TCRs that target defined peptide epitopes would be of considerable utility but has up until now been unsuccessful. Here, we develop an artificial intelligence (AI)-powered approach using a hybrid physics-based simulation and generative AI that successfully engineers TCRs against defined epitopes presented by MHC-I. We use this approach to design TCRs against two cancer antigens, a HERC1 neoantigen and an immunogenic neoepitope in mutant EGFR. We engineer multiple TCRs against the HERC1 neoantigen which activate T cells in response to exposure to peptide-MHC I and kill cancer cells more effectively than a patient-derived TCR. In addition, we used generative AI to design functional TCRs that target the EGFR T790M neoantigen, engineering greater specificity against the mutant sequence. We present an AI-based approach to TCR design with broad utility for efforts to engineer TCRs and for the development of new cell therapies. One sentence summaryArtificial intelligence-based approach enables the directed engineering of functional TCRs with enhanced features that target cancer neoantigens.

immunology↗

bioRxiv2025

Platelets drive immune suppression and glioblastoma growth in a sex-dependent manner via PAR4 signaling

Sex differences in cancer outcome, including that of glioblastoma (GBM), are shaped by biological, hormonal, and immunological factors and impact disease progression, treatment responses, survival, and tumor microenvironment (TME) interactions. Platelets regulate the immune responses and tumor progression in many cancers, but it is not clear how they contribute to these sex-based differences by affecting the dynamics of the TME. Here, we show that GBM patients exhibit heightened platelet reactivity driven by PAR4 signaling. In murine GBM models, both pharmacological inhibition of PAR4 using BMS986120 and genetic deletion of PAR4 significantly prolong survival in females but not males. This survival advantage is estrogen dependent: it is preserved in chromosomal male-hormonal female mice within the four-core genotype model and is rescued in ovariectomized mice treated with estrogen. The survival benefit is TME specific and is mediated by platelet-driven enhancement of CD8 T cell infiltration into the tumor. Inhibition of platelet PAR4 signaling increases calcium signaling through an estrogen-dependent interaction between PAR4 and estrogen receptor {beta} (ER{beta})--a receptor interaction not previously described. PAR4-activated platelets within the TME suppress CD8 T cell function, and depletion of CD8 T cells abolishes both the tumor-induced platelet reactivity and the survival benefit conferred by PAR4 inhibition. These findings establish platelet-mediated PAR4 signaling as a critical driver of tumor progression and identify sex-specific immune responses as key to therapeutic efficacy.

cancer biology↗

bioRxiv2025

Single Cell RNA-sequencing of BCG naive and recurrent non-muscle invasive bladder cancer reveals a CD6/ALCAM mediated immune-suppressive pathway

Non-muscle invasive bladder cancer (NMIBC) represents 70-80% patients with newly diagnosed bladder cancer, and Bacillus Calmette-Guerin (BCG) remains a cornerstone treatment for intermediate-and high-risk NMIBC to prevent disease recurrence and progression. However, many patients experience recurrence after induction BCG, posing significant challenges in the management of the disease. We conducted single cell RNA sequencing on freshly collected NMIBC samples, distinguishing between those naive to BCG treatment and those that recurred post-BCG treatment. We observed a clear activation of inflammatory pathways across cell types during recurrence, but these were not associated with canonical immune checkpoint or T cell exhaustion phenotypes. Analysis of cell-to-cell communication revealed enhanced interactions between T cells and urothelial cells in BCG-recurrence, predominantly modulated by CD6 and ALCAM. Furthermore, we found CD6hi T cells to be immunosuppressed and enriched in recurrent samples, suggesting a potential role for CD6 as an immune evasion signal in NMIBC. SIGNIFICANCEThese findings uncover a novel mechanism responsible for bladder cancer recurrence after BCG treatment. Enhanced T cell-urothelial cell communication in recurrent tumors mediated by CD6 and ALCAM leads to an immunosuppressed state. Thus, CD6 may have potential as a therapeutic target to augment BCG response in non-muscle invasive bladder cancer.

cancer biology↗

bioRxiv2022

The MIF SNP rs755622 is a germline determinant of tumor immune activation in Glioblastoma

While immunotherapies have shown durable responses for multiple tumors, their efficacy remains limited in some advanced cancers, including glioblastoma. This may be due to differences in the immune landscape, as the glioblastoma microenvironment strongly favors immunosuppressive myeloid cells, which are linked to an elevation in immune-suppressive cytokines, including macrophage migration inhibitory factor (MIF). We now find that a single-nucleotide polymorphism (SNP) rs755622 in the MIF promoter associates with increased leukocyte infiltration in glioblastoma. Furthermore, we identified lactotransferrin expression as being associated with the rs755622 SNP, which could also be used as a biomarker for immune infiltrated tumors. These findings provide the first example in glioblastoma of a germline SNP that underlies differences in the immune microenvironment and identifies high lactotransferrin as a potential factor promoting immune activation.

cancer biology↗

bioRxiv2020

Single-Cell Analysis of Hyperthermic Intraperitoneal Chemotherapy Treated Tumors Reveals Distinct Cellular and Molecular Responses

Hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a clinical regimen that prolongs overall survival for patients with advanced Epithelial Ovarian Cancer (EOC). However, the mechanism of action of HIPEC remains poorly understood. To provide insights into the rapid changes that accompany HIPEC, tumors from five patients with high grade serous ovarian cancer were harvested from the omentum at time of debulking and after 90 minutes of HIPEC treatment. Specimens were rapidly dissociated into single cells and processed for single cell RNA-seq. Unbiased clustering identified 19 cell clusters that were annotated based on cellular transcriptome signatures to identify the epithelial, stromal, T and B immune cells, macrophages, and natural killer cell populations. Hallmark pathway analysis revealed heat shock, metabolic reprogramming, inflammatory, and EMT pathway enrichment in distinct cell populations upon HIPEC treatment. Collectively, our findings provide the foundation for mechanistic studies focused on how HIPEC orchestrates the ovarian cancer tissue response.

cancer biology↗

bioRxiv2019

Glioblastoma myeloid-derived suppressor cell subsets express differential macrophage migration inhibitory factor receptor profiles that can be targeted to reduce immune suppression

The application of tumor immunotherapy to glioblastoma (GBM) is limited by an unprecedented degree of immune suppression due to factors that include high numbers of immune suppressive myeloid cells, the blood brain barrier, and T cell sequestration to the bone marrow. We previously identified an increase in immune suppressive myeloid-derived suppressor cells (MDSCs) in GBM patients, which correlated with poor prognosis and was dependent on macrophage migration inhibitory factor (MIF). Here we examine the MIF signaling axis in detail in murine MDSC models, GBM-educated MDSCs and human GBM. We found that the monocytic subset of MDSCs (M-MDSCs), expressed high levels of the MIF cognate receptor CD74 and was localized in the tumor microenvironment. In contrast, granulocytic MDSCs (G-MDSCs) expressed high levels of the MIF non-cognate receptor CXCR2 and showed minimal accumulation in the tumor microenvironment. Furthermore, targeting M-MDSCs with ibudilast, a brain penetrant MIF-CD74 interaction inhibitor, reduced MDSC function and enhanced CD8 T cell activity in the tumor microenvironment. These findings demonstrate the MDSC subsets differentially express MIF receptors and may be leveraged for specific MDSC targeting.

immunology↗

bioRxiv2019

ADAMDEC1 maintains a novel growth factor signaling loop in cancer stem cells

Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSCs), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs. This loop consists of an atypical metalloproteinase, a disintegrin and metalloproteinase domain-like protein decysin 1 (ADAMDEC1), secreted by GSCs. ADAMDEC1 rapidly solubilizes fibroblast growth factor-2 (FGF2) to stimulate FGF receptor 1 (FGFR1) expressed on GSCs. This signaling axis induces upregulation of Zinc finger E-box-binding homeobox 1 (ZEB1) that regulates ADAMDEC1 expression, creating a positive feedback loop. Genetic or pharmacological targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signaling axis for GSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GBM. Statement of SignificanceCancer stem cells (CSC) drive tumor growth in many cancers including glioblastoma. We identified a novel sheddase, a disintegrin and metalloproteinase domain-like protein decysin 1, that initiates a fibroblast growth factor autocrine loop to promote stemness in CSCs. This loop can be targeted to reduce glioblastoma growth.

cancer biology↗

bioRxiv2018

Development of a Cx46 targeting strategy for cancer stem cells

Gap junction-mediated cell-cell communication enables tumor cells to synchronize the execution of complex processes. Despite the connexin family of gap junction proteins being considered tumor suppressors, we previously found that glioblastoma cancer stem cells (CSCs) express higher levels of Cx46 compared to non-stem tumor cells, and this was necessary and sufficient for CSC maintenance. To develop a Cx46 targeting strategy, we utilized point mutants to disrupt specific functions of Cx46 and found that gap junction coupling was the critical function of Cx46 for CSCs. Based on this finding, we screened a clinically relevant library of small molecules and identified clofazimine as an inhibitor of Cx46-specific cell-cell communication. Clofazimine attenuated proliferation, self-renewal, and tumor growth and synergized with temozolomide to induce apoptosis. These data suggest that combining clofazimine with standard-of-care therapies may target glioblastoma CSCs. Furthermore, these results demonstrate the importance of targeting cell-cell communication as an anti-cancer therapy.

cancer biology↗