Telomerase deficiency and dysfunctional telomeres in the lung tumor microenvironment impair tumor progression in NSCLC mouse models and patient-derived xenografts

by Selleckchem | Jun 26 2023

Non-small cell lung cancer (NSCLC) is a leading cause of cancer death. Tumor progression depends on interactions of cancer cells with the tumor microenvironment. Here, we find increased copy number and mRNA expression of the catalytic subunit of telomerase, TERT, in tumors from NSCLC patients, contributing to a lower survival. Moreover, TERT expression in NSCLC patients from the TCGA cohort is mainly associated to the reduced infiltration of CD8+ T lymphocytes, as well as to increased infiltration of myeloid-derived suppressor cells (MDSCs). We also show that TERT deficiency and dysfunctional telomeres induced by 6-thio-dG treatment in mice reduced lung tumor implantation and vascularization, increased DNA damage response, cell cycle arrest and apoptosis, as well as reduced proliferation, inflammation, lung tumor immunosupression and invasion upon induction of a Lewis lung carcinoma (LLC). Furthermore, 6-thio-dG-treated human NSCLC xenografts exhibited increased telomere damage, cell cycle arrest and apoptosis, as well as reduced proliferation, resulting in a reduced tumor growth. Our results show that targeting telomeres might be an effective therapeutic strategy in NSCLC.

Comments:

The information you provided describes a study that investigates the role of the catalytic subunit of telomerase, TERT, in non-small cell lung cancer (NSCLC) and its interactions with the tumor microenvironment. Here are the key findings of the study:

Increased copy number and mRNA expression of TERT: The researchers found higher levels of TERT in tumors from NSCLC patients. This increase in TERT expression was associated with lower survival rates.

Association with immune cell infiltration: TERT expression in NSCLC patients from the TCGA cohort was primarily linked to reduced infiltration of CD8+ T lymphocytes, which are important for antitumor immune responses. Additionally, there was an increased infiltration of myeloid-derived suppressor cells (MDSCs), which are known to suppress immune responses.

TERT deficiency and dysfunctional telomeres: The study utilized a mouse model and treated the mice with 6-thio-dG, a compound that induces telomere dysfunction and TERT deficiency. This treatment resulted in reduced lung tumor implantation and vascularization, increased DNA damage response, cell cycle arrest, and apoptosis. It also led to reduced proliferation, inflammation, immunosuppression, and invasion in a model of Lewis lung carcinoma (LLC).

Effects on human NSCLC xenografts: Human NSCLC xenografts treated with 6-thio-dG exhibited increased telomere damage, cell cycle arrest, and apoptosis. This treatment also reduced proliferation, resulting in reduced tumor growth.

Based on these findings, the study suggests that targeting telomeres could be an effective therapeutic strategy for NSCLC. By inducing telomere dysfunction and reducing TERT activity, it may be possible to inhibit tumor growth, enhance DNA damage response, promote cell cycle arrest and apoptosis, and reduce inflammation and immunosuppression in NSCLC. However, it's important to note that further research and clinical trials are necessary to validate these findings and determine the feasibility of telomere-targeted therapies in NSCLC.