Targeted Inhibition of lncRNA Malat1 Alters the Tumor Immune Microenvironment in Preclinical Syngeneic Mouse Models of Triple-Negative Breast Cancer

Authors

Oluwatoyosi Adewunmi
Yichao Shen
Xiang H-F Zhang
Jeffrey M Rosen

Publication Date

11-1-2023

Journal

Cancer Immunology Research

DOI

10.1158/2326-6066.CIR-23-0045

PMID

37603945

PMCID

PMC10618655

PubMedCentral® Posted Date

8-21-2023

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Humans, Animals, Mice, RNA, Long Noncoding, Triple Negative Breast Neoplasms, Tumor Microenvironment, Gene Expression Regulation, Neoplastic, Cell Proliferation, Adenocarcinoma, Cell Line, Tumor

Abstract

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 (Malat1) is an abundant lncRNA whose expression is upregulated in several cancers. Although Malat1 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 Malat1 and the tumor immune microenvironment (TIME) using several immune-competent preclinical syngeneic Tp53-null triple-negative breast cancer (TNBC) mouse models that mimic the heterogeneity and immunosuppressive TME found in human breast cancer. Using a Malat1 ASO, we were able to knockdown Malat1 RNA expression resulting in a delay in primary tumor growth, decreased proliferation, and increased apoptosis. In addition, immunophenotyping of tumor-infiltrating lymphocytes revealed that Malat1 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+ T cells. Malat1 depletion in tumor cells, TAMs, and MDSCs decreased immunosuppressive cytokine/chemokine secretion whereas Malat1 inhibition in T cells increased inflammatory secretions and T-cell proliferation. Combination of a Malat1 ASO with chemotherapy or immune checkpoint blockade (ICB) improved the treatment responses in a preclinical model. These studies highlight the immunostimulatory effects of Malat1 inhibition in TNBC, the benefit of a Malat1 ASO therapeutic, and its potential use in combination with chemotherapies and immunotherapies.

Comments

Associated Data