Biology subjects

Torres-Mejia, E.

Publications and source records attributed to Torres-Mejia, E..

2 recordsLinked to original sources

bioRxiv2026

Modeling lung adenocarcinoma using layer-by-layer nanoparticles mitigates innate immune cell activation

Lung adenocarcinoma, driven frequently by KRAS and p53 mutations, remains a leading cause of cancer mortality. Current state-of-the-art genetically engineered mouse models often rely on viral delivery of recombinases, such as Cre recombinase, to initiate transformation. However, viral particles can infect and activate innate immune cells, thus potentially impacting studies of tumor-immune dynamics. Here, we develop a layer-by-layer (LbL) polyplex platform using poly({beta}-aminoester) (PBAE) polymers layered with poly-L-aspartic acid (PLD) to deliver Cre mRNA to lungs while avoiding immune cell transfection and activation. PLD-coated nanoparticles (PLD-NPs) exhibit stable mRNA encapsulation and efficient transfection in vitro, even after lyophilization and long-term storage. In KrasLSL-G12D/+;p53flox/flox (KP) mice, PLD-NPs initiate lung adenocarcinomas that mirror human histopathology without infecting or activating dendritic cells and alveolar macrophages, unlike lentiviral (LV) or adenoviral delivery methods. Single-cell transcriptional profiling revealed that LV administration drives long-term upregulation of antigen presentation and costimulatory machinery in lung-resident myeloid populations. This persistent immune activation is avoided by NP delivery. By uncoupling tumor initiation from innate immune activation, this platform enables the high-fidelity interrogation of tumor-immune dynamics, especially for non-inflammation-driven lung cancer.

immunology↗

bioRxiv2023

Lung cancer-intrinsic SOX2 expression mediates resistance to checkpoint blockade therapy by inducing Treg-dependent CD8+ T cell exclusion

Tumor-intrinsic signaling pathways can drastically affect the tumor immune microenvironment (TME), promoting tumor progression and resistance to immunotherapy by excluding immune cell populations from the tumor. Several tumor-cell intrinsic pathways have been reported to affect myeloid cell infiltration and downstream T cell infiltration. Clinical evidence suggests that the exclusion of cytotoxic T cells from the tumor core likewise mediates resistance. Here, we find that tumor cell-intrinsic SOX2 expression induces the exclusion of cytotoxic T cells from the tumor core and promotes resistance to checkpoint blockade therapy. CD8+ T cell exclusion was dependent on regulatory T cell-mediated suppression of tumor vasculature. Depleting tumor-infiltrating regulatory T cells via Glucocorticoid-Induced TNFR-Related (GITR) restored CD8+ T cell infiltration and reduced tumor growth in combination with checkpoint blockade therapy. SignificanceWe identified tumor cell-intrinsic SOX2 expression in lung cancer as a mechanism of resistance to immunotherapy. SOX2 expression increases regulatory T cell populations in the TME, negatively affecting the tumor vasculature and blunting CD8+ T cell infiltration into the tumor core. This effect could be reverted by targeting regulatory T cells with anti-GITR therapy.

immunology↗