Data from Targeted Inhibition of lncRNA <i>Malat1</i> Alters the Tumor Immune Microenvironment in Preclinical Syngeneic Mouse Models of Triple-Negative Breast Cancer

Abstract

<div>Abstract<p>Long noncoding RNAs (lncRNA) play an important role in gene regulation in both normal tissues and cancer. Targeting lncRNAs is a promising therapeutic approach that has become feasible through the development of gapmer antisense oligonucleotides (ASO). Metastasis-associated lung adenocarcinoma transcript (<i>Malat1</i>) is an abundant lncRNA whose expression is upregulated in several cancers. Although <i>Malat1</i> increases the migratory and invasive properties of tumor cells, its role in the tumor microenvironment (TME) is still not well defined. We explored the connection between <i>Malat1</i> and the tumor immune microenvironment (TIME) using several immune-competent preclinical syngeneic <i>Tp53</i>-null triple-negative breast cancer (TNBC) mouse models that mimic the heterogeneity and immunosuppressive TME found in human breast cancer. Using a <i>Malat1</i> ASO, we were able to knockdown <i>Malat1</i> RNA expression resulting in a delay in primary tumor growth, decreased proliferation, and increased apoptosis. In addition, immunophenotyping of tumor-infiltrating lymphocytes revealed that <i>Malat1</i> inhibition altered the TIME, with a decrease in immunosuppressive tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) as well as an increase in cytotoxic CD8<sup>+</sup> T cells. <i>Malat1</i> depletion in tumor cells, TAMs, and MDSCs decreased immunosuppressive cytokine/chemokine secretion whereas <i>Malat1</i> inhibition in T cells increased inflammatory secretions and T-cell proliferation. Combination of a <i>Malat1</i> ASO with chemotherapy or immune checkpoint blockade (ICB) improved the treatment responses in a preclinical model. These studies highlight the immunostimulatory effects of <i>Malat1</i> inhibition in TNBC, the benefit of a <i>Malat1</i> ASO therapeutic, and its potential use in combination with chemotherapies and immunotherapies.</p></div>