Abstract 3480: Modulating DNA and histone methylation as a therapeutic target for non-small cell lung cancer by shifting the composition of immune cells
Authors: Chen Ying-Yu 
Published: April 2023

Lung cancer is one of the most common malignancies worldwide with non-small cell lung cancer (NSCLC) being the dominant subtype. Surgical resection remains the best treatment for NSCLC, but late diagnosis with associated metastasis precludes this as a viable modality for most patients. Furthermore, other treatments such as targeted therapies, cytotoxics, and immunotherapy only benefit a minority of patients. Therefore, new therapeutic strategies are needed to benefit more patients presenting with this devastating disease. Recent studies reveal that DNMT inhibitor (DNMTi) promotes tumor-infiltrative cytotoxic CD8+ T cells, shifts myeloid-derived suppressor cells (MDSCs) to anti-tumor macrophage-like phenotype, and enhances immunotherapy efficacy. However, some immune-regulatory genes are silenced by H3K27me3, which is facilitated by the transcriptional repressor EZH2. Additionally, conditional ablation of Ezh2 in T cells boosts effector functions of CD8+ T cells and prevents the development of regulatory T cells. Given the above, the application of combining DNMTi and EZH2i might be a viable path to facilitate tumor immune microenvironment remodeling.

In this study, we aimed to define the therapeutic potential of combining DNMT and EZH2 inhibition to facilitate an anti-tumor immune response. First, we explored the potential of combined DNMTi and EZH2i in a clinically relevant murine model of NSCLC, Lewis Lung Carcinoma 1 (LLC1). Therapeutic application in this model led to a significant reduction in tumor volume. Our transcriptomic data revealed DNMTi facilitated transcriptional perturbation of both coding and transposable element-related genes, which is driven further by EZH2i combination. Immune deconvolution analysis uncovers combination therapy-induced shifts in tumor immune-cellularity, which is most profound for myeloid-associated populations. Orthogonal validation by flow cytometry defines significant reductions of MDSCs and regulatory T cells occurring within the tumor and associated microenvironment.

Given the perturbations of T and myeloid cells observed in-vivo, we sought to define the drug effects on critical cell populations contained in these lineages. These data revealed that combining DNMTi and EZH2i promotes effector CD8+ T cells with more IFN-g secretion upon activation but halts the cells from exhaustion after chronic stimulation. Moreover, co-treatment promoted maturation, cross-presentation, and antigen-specific CD8+ T cell priming in dendritic cells (DCs). These data indicate that CD8+ T cells and DCs subjected to co-treatment might facilitate more robust tumor immune responses in the tumor microenvironment (TME). In summary, our data define an effective therapeutic paradigm for the treatment of NSCLC, which potentiates significant shifts in TME resident immune populations and dendritic cell phenotypes.

Citation Format: Ying-Yu Chen. Modulating DNA and histone methylation as a therapeutic target for non-small cell lung cancer by shifting the composition of immune cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3480.