Clonally Expanded T Cells Reveal Immunogenicity of Rhabdoid Tumors

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Rhabdoid tumors (RTs) are aggressive pediatric cancers characterized by SMARCB1 gene inactivation.
• This inactivation leads to a deficient SWI/SNF chromatin remodeling complex, impacting tumor biology.
• Understanding the tumor immune microenvironment is crucial for developing effective therapies.

Purpose of the Study:

• To comprehensively evaluate the immune infiltrates in human and mouse RTs.
• To identify potential therapeutic targets within the tumor immune microenvironment.
• To elucidate mechanisms underlying RT immunogenicity.

Main Methods:

• Immunohistochemistry, bulk RNA sequencing, and DNA methylation profiling of RTs.
• Single-cell RNA (scRNA) and T cell receptor (TCR) sequencing.
• Checkpoint blockade therapy in a preclinical RT model.

Main Results:

• RTs are highly infiltrated by T cells and myeloid cells.
• scRNA and TCR sequencing revealed distinct CD8+ T cell subpopulations, including exhausted and tissue-resident memory cells.
• Checkpoint blockade therapy led to tumor regression and sustained immune memory.
• SMARCB1 loss promotes RT immunogenicity via endogenous retroviral re-expression and interferon signaling.

Conclusions:

• RTs possess a complex immune microenvironment with therapeutically targetable T cell populations.
• SMARCB1-dependent mechanisms contribute to RT immunogenicity.
• Checkpoint blockade is a promising therapeutic strategy for RTs.