Locus-Specific Human Endogenous Retrovirus ERVK18 Expression Indicates an Inflamed Microenvironment and Favorable...

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Immunotherapy has advanced small cell lung cancer (SCLC) treatment, but predictive biomarkers are scarce.
• Human endogenous retrovirus-K (HERV-K) influences immune responses in various cancers, yet its role in SCLC is unclear.
• Understanding HERV-K's association with SCLC's immune microenvironment and immunotherapy response is crucial.

Purpose of the Study:

• To investigate the prognostic and predictive value of HERV-K transcripts in SCLC immunotherapy.
• To explore the relationship between HERV-K expression, tumor immune microenvironment, and clinical outcomes in SCLC patients.

Main Methods:

• Locus-specific HERV-K expression was analyzed using TELESCOPE in SCLC cohorts (IMpower133, PKUPH).
• Immunohistochemistry and RNA-FISH validated HERV-K transcript expression.
• Single-cell RNA sequencing and multiplex immunohistochemistry characterized the tumor immune microenvironment.

Main Results:

• While HERV-K as a whole lacked prognostic value, the ERVK18 transcript correlated with improved SCLC immunotherapy outcomes.
• High ERVK18 expression was linked to immune-related signatures, increased immune cell infiltration, and enhanced T-cell cytotoxicity.
• ERVK18 predicted better survival in patients receiving atezolizumab plus chemotherapy versus chemotherapy alone in the IMpower133 cohort.

Conclusions:

• Elevated ERVK18 expression signifies an inflamed tumor microenvironment in SCLC.
• ERVK18 serves as a dual prognostic and predictive biomarker for first-line immunotherapy response in SCLC.