Biology subjects

Nabet, B. Y.

Publications and source records attributed to Nabet, B. Y..

4 recordsLinked to original sources

bioRxiv2025

T CELLS promote the growth of small-cell lung carcinoma via an IL-6/CD74 axis

A central challenge in immuno-oncology is overcoming the limited efficacy and durability of immune checkpoint inhibition (ICI). This is particularly true in small-cell lung cancer (SCLC), where chemotherapy plus ICI is standard of care but rarely curative. Here, we found that T cells are surprisingly both necessary and sufficient for optimal tumor growth in mouse models of SCLC. These pro-tumoral effects are mediated by interleukin-6 (IL-6) production, which induces the pro-survival factor CD74 in SCLC cells. Notably, T cells within human SCLC tumors express IL-6, and low IL-6 signaling correlates with improved survival following chemotherapy plus ICI in patients. Accordingly, IL-6 blockade synergizes with ICI to inhibit SCLC growth in vivo. These findings reveal a paradoxical role for T cells in SCLC, uncovering an unexpected T cell-IL-6-CD74 axis that promotes tumor survival, and identify IL-6 as a promising target to help unleash the full potential of immunotherapy in this aggressive cancer.

cancer biology↗

bioRxiv2025

Human Lung Alveolar Model with an Autologous Innate and Adaptive Immune Compartment

Lung-resident immune cells, spanning both innate and adaptive compartments, preserve the integrity of the respiratory barrier, but become pathogenic if dysregulated1. Current in vitro organoid models aim to replicate interactions between the alveolar epithelium and immune cells but have not yet incorporated lung-specific immune cells critical for tissue residency2. Here we address this shortcoming by describing human lung alveolar immuno-organoids (LIO) that contain an autologous tissue-resident lymphoid compartment, primarily composed of tissue-resident memory T cells (TRMs). Additionally, we introduce lung alveolar immuno-organoids with myeloid cells (LIOM), which include both TRMs and a macrophage-rich alveolar myeloid compartment. The resident immune cells formed a stable immune-epithelial system, frequently interacting with the epithelium and promoting a regenerative alveolar transcriptomic profile. To understand how dysregulated inflammation perturbed the respiratory barrier, we simulated T-cell-mediated inflammation in LIOs and LIOMs and used single-cell transcriptomic analyses to uncover the molecular mechanisms driving immune responses. The presence of innate cells induced a shift in T cell identity from cytotoxic to immunosuppressive, reducing epithelial cell killing and inflammation. Based on insights obtained with bulk RNA-seq data from the phase 3 IMpower150 trial, we tested whether LIOM cultures could model clinically-relevant but poorly understood pulmonary side effects caused by immunotherapies such as the checkpoint inhibitor atezolizumab3. We observed a decrease in immunosuppressive T cells and identified gene signatures that matched the transcriptomic profile of patients with drug-induced pneumonitis. Given its effectiveness in capturing outcomes and mechanisms associated with a prevalent pulmonary disease, this system unlocks opportunities for studying a wide range of immune-related pathologies in the lung.

cell biology↗

bioRxiv2024

DNA damage response signatures are associated with frontline chemotherapy response and routes of tumor evolution in extensive stage small cell lung cancer

IntroductionA hallmark of small cell lung cancer (SCLC) is its recalcitrance to therapy. While most SCLCs respond to frontline therapy, resistance inevitably develops. Identifying phenotypes potentiating chemoresistance and immune evasion is a crucial unmet need. Previous reports have linked upregulation of the DNA damage response (DDR) machinery to chemoresistance and immune evasion across cancers. However, it is unknown if SCLCs exhibit distinct DDR phenotypes. MethodsTo study SCLC DDR phenotypes, we developed a new DDR gene analysis method and applied it to SCLC clinical samples, in vitro, and in vivo model systems. We then investigated how DDR regulation is associated with SCLC biology, chemotherapy response, and tumor evolution following therapy. ResultsUsing multi-omic profiling, we demonstrate that SCLC tumors cluster into three DDR phenotypes with unique molecular features. Hallmarks of these DDR clusters include differential expression of DNA repair genes, increased replication stress, and heightened G2/M cell cycle arrest. SCLCs with elevated DDR phenotypes exhibit increased neuroendocrine features and decreased "inflamed" biomarkers, both within and across SCLC subtypes. Treatment naive DDR status identified SCLC patients with different responses to frontline chemotherapy. Tumors with initial DDR Intermediate and DDR High phenotypes demonstrated greater tendency for subtype switching and emergence of heterogeneous phenotypes following treatment. ConclusionsWe establish that SCLC can be classified into one of three distinct, clinically relevant DDR clusters. Our data demonstrates that DDR status plays a key role in shaping SCLC phenotypes, chemotherapy response, and patterns of tumor evolution. Future work targeting DDR specific phenotypes will be instrumental in improving patient outcomes.

cancer biology↗

bioRxiv2022

T cell-instructed inflammation drives immune checkpoint inhibitor therapy resistance

Resistance to immune checkpoint inhibitors (ICIs) is common, even in tumors with T cell infiltration. We thus investigated consequences of ICI-induced T cell infiltration in the microenvironment of resistant tumors. T cells increased in ICI-resistant tumors following treatment as did neutrophils, in contrast to ICI-responsive tumors. Resistant tumors were distinguished by high expression of IL-1 Receptor 1 (IL1R1), enabling a synergistic response to IL-1 and TNF to induce G-CSF, CXCL1, and CXCL2 via NF-{kappa}B signaling, supporting neutrophils. Perturbation of this inflammatory resistance circuit sensitized tumors to ICIs. Paradoxically, T cells drove this resistance circuit via TNF both in vitro and in vivo. Evidence of this inflammatory resistance circuit and its impact also translated to human cancers. These data support a novel mechanism of ICI resistance, wherein treatment-induced T cell activity can drive resistance in tumors responsive to IL-1 and TNF, with important therapeutic implications. Statement of SignificanceAlthough T cell-infiltrated cancers are frequently resistant to immune checkpoint inhibitor therapies, mechanisms of resistance beyond T cell exhaustion remain unclear. Here, we reveal the functional significance of tumor- infiltrating T cells in resistant tumors, which surprisingly instruct immunosuppressive inflammation in mouse and human cancers responsive to IL-1 and TNF.

immunology↗