Biology subjects

Brainson, C. F.

Publications and source records attributed to Brainson, C. F..

4 recordsLinked to original sources

bioRxiv2026

EZH1/2 inhibition improves immunotherapy response through MHC Class II de-repression and neutrophil reprogramming

Squamous cell carcinoma of the lung is a difficult-to-treat cancer with high prevalence in the US, and particularly in Kentucky. Here, we sought to test if the EZH1/2 inhibitor valemetostat improves anti-PD1 responses in squamous cell lung cancer models, and to develop ex vivo models to test immunotherapy drug combinations. We found that valemetostat augmented anti-tumor responses to anti-PD1 therapy, led to up-regulation of tumor cell specific Major Histocompatibility Complex Class II (MHC Class II), and drove systemic neutrophil maturation. Likewise, Ezh2 knock-out mice produced neutrophils that were more apoptotic, less migratory, and less able to produce extracellular nets, but had similar ability to kill bacteria as Ezh2-WT neutrophils. To test tumor responses to differing neutrophil populations, we engineered three-dimensional air-liquid interface cultures with tumoroids, lung mesenchymal cells, and T cells, with and without bone marrow containing neutrophils and myeloid progenitors from distinct donors. Bone marrow from tumor-naive or mice with actively growing untreated tumors boosted tumoroid growth, while bone marrow from spontaneously tumor-rejected or mice with tumors treated with valemetostat was anti-tumor. MHC Class II blockade lowered the ability of bone marrow to boost tumor growth, and reduced the ability of valemetostat with anti-PD1 to reduce tumoroid growth. Patient samples revealed a strong negative correlation between EZH2 and MHC Class II, suggesting that targeting EZH2 activity could lead to marked increase in MHC Class II and improve treatment responses in lung squamous cell carcinomas.

cancer biology↗

bioRxiv2025

Single-cell profiling of EZH2-mediated immune signaling perturbations in NSCLC

Lung cancer, the leading cause of cancer-related death in the United States, remains a significant public health burden. One of the most personalized treatments to date uses a patients own tumor-infiltrating lymphocytes (TILs) as a cellular therapy to target the tumor. Endogenous TIL activity is also essential for immune checkpoint inhibitor (ICI) effectiveness. However, responses to immunotherapies vary due to immune-suppressive tumor microenvironments (TMEs) and limited antigen presentation. In this study, we computationally examine cell-cell signaling and transcriptional activity using single-cell RNA sequencing of lung cancer treated by inhibiting methyltransferase EZH2. We show that EZH2 inhibition shifts the TME to immunogenic signaling patterns conducive to increased T cell response, including antigen presentation and homing. T cells also showed more stem-like phenotypes. Importantly, inferred EZH2 activity showed it can still perform non-methyltransferase duties that are vital for T cell differentiation. Lastly, we tested our findings with patient-derived NSCLC TILs and found that transient EZH1/2 inhibition with valemetostat prior to harvest increases the CD8:CD4 ratio and T cell reactivity, but preferentially expands effector memory rather than central memory populations. These results indicate that transitory EZH2 inhibition could improve immunotherapies for lung cancer patients, with additional optimization needed to maximize TIL therapeutic benefit.

bioinformatics↗

bioRxiv2024

Methionine Restriction Reduces Lung Cancer Progression and Increases Chemotherapy Response

Targeting tumor metabolism through dietary interventions is an area of growing interest, and may help to improve the significant mortality of aggressive cancers, including non-small cell lung cancer (NSCLC). Here we show that the restriction of methionine in the aggressive KRAS/Lkb1-mutant NSCLC autochthonous mouse model drives decreased tumor progression and increased carboplatin treatment efficacy. Importantly, methionine restriction during early stages of tumorigenesis prevents the lineage switching known to occur in the model, and alters the tumor immune microenvironment (TIME) to have fewer tumor-infiltrating neutrophils. Mechanistically, mutations in LKB1 are linked to anti-oxidant production through changes to cystathionine-{beta}-synthase (CBS) expression. Human cell lines with rescued LKB1 show increased CBS levels and resistance to carboplatin, which can be partially rescued by methionine restriction. Furthermore, LKB1 rescued cells, but not mutant cells, show less G2- M arrest and apoptosis in high methionine conditions. Knock-down of CBS sensitized both LKB1 mutant and non-mutated lines to carboplatin, again rescuing the carboplatin resistance of the LKB1 rescued lines. Given that immunotherapy is commonly combined with chemotherapy for NSCLC, we next wanted to understand if T cells are impaired by MR. Therefore, we examined the ability of T cells from MR and control tumor bearing mice to proliferate in culture and found that T cells from MR treated mice had no defects in proliferation, even though we continued the MR conditions ex vivo. We also identified that CBS is most highly correlated with smoking, adenocarcinomas with alveolar and bronchiolar features, and adenosquamous cell carcinomas, implicating its roles in oxidative stress response and lineage fate in human tumors. Taken together, we have shown the importance of MR as a dietary intervention to slow tumor growth and improve treatment outcomes for NSCLC.

cancer biology↗

bioRxiv2023

EZH2 inhibition promotes tumor immunogenicity in lung squamous cell carcinomas

Two important factors that contribute to resistance to immune checkpoint inhibitors (ICIs) are an immune-suppressive microenvironment and limited antigen presentation by tumor cells. In this study, we examine if inhibition of the methyltransferase EZH2 can increase ICI response in lung squamous cell carcinomas (LSCCs). Our in vitro experiments using 2D human cancer cell lines as well as 3D murine and patient derived organoids treated with two inhibitors of the EZH2 plus interferon-{gamma} (IFN{gamma}) showed that EZH2 inhibition leads to expression of both major histocompatibility complex class I and II (MHCI/II) expression at both the mRNA and protein levels. ChIP-sequencing confirmed loss of EZH2-mediated histone marks and gain of activating histone marks at key loci. Further, we demonstrate strong tumor control in models of both autochthonous and syngeneic LSCC treated with anti-PD1 immunotherapy with EZH2 inhibition. Single-cell RNA sequencing and immune cell profiling demonstrated phenotypic changes towards more tumor suppressive phenotypes in EZH2 inhibitor treated tumors. These results indicate that this therapeutic modality could increase ICI responses in patients undergoing treatment for LSCC.

cancer biology↗