Exploiting transposon reactivation and mitochondrial dysregulation to improve immune recognition in lung adenocarcinoma

The immunotherapy approach has become the “fourth pillar” of lung adenocarcinoma (LUAD) treatment. Currently, PD1/PD-L1 expression, tumor mutational burden, and microsatellite instability are the available indicators of a good response to immunotherapy. However, because those cannot fully reflect the heterogeneity of the tumor immunological microenvironment (TIME) and the associated defense mechanisms, only a limited proportion of patients benefit from checkpoint inhibitor (CPI) immunotherapies. The development of prognostic models and new biomarkers are essential to improve the prediction of LUAD progression and the therapeutic effect of CPI.

A variety of factors have been shown to influence TIME and inflammatory mediators are known to contribute to recruitment of effector immune cells. Increasingly recognized sources for cytoplasmatic dsRNA and DNA are reactivation and expression of transposons and leakage of mitochondrial DNA or RNA from damaged mitochondria which activate a variety of different pathways of the innate immune response and lead to robust IFN-I responses. One of the main mediators of transposon silencing is the lysine-specific histone demethylase (LSD1). LSD1 inhibition leads to transposon reactivation and mitochondrial injury. Targeting LSD1 in combination with anti-PD-(L)1 expression, analysis of mitochondrial injury and transposon reactivation could prove to be a broadly applicable new strategy in  LUAD   immunotherapy.

Translationale Molekularpathologie - AG Odenthal - Forschung | Pathologie Uniklinik Köln (uk-koeln.de)