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Expression of down-regulated ERV LTR elements associates with immune activation in human small-cell lung cancers
Marco Russo1, Sara Morelli1, Giovanni Capranico2
1Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, via Selmi 3, 40126, Bologna, Italy.
Abstract:
Small-cell lung cancer (SCLC) is an aggressive cancer characterized by immunosuppressive features leading to poor responses to current immunotherapies. Activation of transposable elements (TE) can trigger an innate immune response, which can synergize with immunotherapeutic protocols in patients. However, TE activity in relation to immune gene response is not fully known in human SCLC. Here, we compared TE expression in 104 human SCLC and 24 normal tissues and established their involvement in innate immune responses. We observed that different intergenic TEs, mainly endogenous retroviral (ERV) families, are deregulated in SCLC. Similarly to other cancers, we detected a subset of LTRs that correlate with innate immune gene signatures and cytosolic RNA sensors, such as RIG-I. These LTRs are downregulated in SCLC tumors vs. normal tissues, and are mainly located at transcriptional repressed regions, marked with H3K4me2 in different cell lines. Analyses of different genomic datasets show that chromatin repression is likely due to de-methylase LSD1 activity. Moreover, high expression levels of ERV LTRs predict a better survival upon chemotherapy of SCLC patients. The findings reveal a specific pattern of TE-mediated activation of innate immune genes in SCLC, which can be exploited to establish more effective immunotherapeutic combinations.
Insights
Transposable elements (TEs), particularly endogenous retroviral (ERV) long terminal repeats (LTRs), are deregulated in small-cell lung cancer (SCLC). Their downregulation correlates with suppressed immune responses but predicts better chemotherapy survival, offering new immunotherapy targets.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Small-cell lung cancer (SCLC) exhibits immunosuppressive traits, limiting immunotherapy efficacy.
- Transposable element (TE) activation can stimulate innate immunity, potentially enhancing cancer treatments.
- The role of TE activity in SCLC immune responses remains largely unexplored.
Purpose of the Study:
- To investigate TE expression patterns in human SCLC.
- To determine the relationship between TE deregulation and innate immune responses in SCLC.
- To explore the prognostic significance of TE expression in SCLC.
Main Methods:
- Comparative analysis of TE expression in 104 SCLC and 24 normal tissues.
- Correlation analysis between TE expression, innate immune gene signatures, and RNA sensors (e.g., RIG-I).
- Genomic and epigenomic analyses (H3K4me2, LSD1 activity) to identify mechanisms of TE regulation.
Main Results:
- Deregulation of intergenic TEs, predominantly endogenous retroviral (ERV) families, was observed in SCLC.
- A subset of long terminal repeats (LTRs) correlated with innate immune genes and was downregulated in SCLC tumors.
- These downregulated LTRs were located in transcriptionally repressed regions, linked to LSD1 activity.
- Higher ERV LTR expression correlated with improved survival in SCLC patients undergoing chemotherapy.
Conclusions:
- SCLC displays a distinct pattern of TE-mediated innate immune gene activation.
- Downregulated ERV LTRs in SCLC are associated with suppressed immune signaling and repressed chromatin.
- ERV LTR expression may serve as a predictive biomarker for chemotherapy response in SCLC.
- Targeting TE-mediated immune responses presents a promising strategy for novel SCLC immunotherapeutic combinations.
