Role of gamma-delta T cells in cancer immunology

Despite their minority status within the T cell community, gamma-delta T cells are increasingly recognized for their dual capability to engage both innate and adaptive immune responses. Moffitt researchers, in collaboration with scientists at Dartmouth College and Duke University, utilized a novel computational algorithm to analyze the gamma-delta T-cell receptor landscape across 11,000 tumors, providing an extensive database that tracks cancer progression and responses to various treatments, particularly immunotherapy.

"It's like finding a needle in a haystack," said Xuefeng Wang, Ph.D., chair of Moffitt's Biostatistics and Bioinformatics Department and the lead contact of the study. "After two years of effort screening approximately 700 billion tumor RNA sequencing reads, our algorithm distilled 3.2 million gamma-delta T-cell reads, highly informative for the study of gamma-delta T-cell clones. Our findings suggest that the diversity and clonality of gamma-delta T cells can significantly impact patient survival and treatment efficacy."

Key findings of the study include:

• Database Creation: The research yielded a comprehensive database of gamma-delta T-cell receptor sequences across multiple cancers, offering a valuable resource for ongoing research into these immune components.
• Potential Biomarkers: The analysis identified several genes that may serve as prognostic biomarkers, varying significantly across different cancer types, including head and neck squamous cell carcinoma and colorectal adenocarcinoma.
• Immunotherapy Response: The study revealed that higher gamma-delta T-cell receptor gene enrichment scores correlate with better responses to immunotherapy, highlighting the need for personalized treatment approaches incorporating gamma-delta T-cell signatures.
• Tumor Microenvironment: The research indicates that gamma-delta T cells are often enriched in tumor microenvironments compared to normal tissues, suggesting they may play a unique role in immune surveillance.
• Context-Specific Roles: The study emphasizes the complexity of gamma-delta T-cell contributions, noting that their impact on disease progression varies based on tumor molecular characteristics and patient context.

As the study evolves, researchers will expand the database by incorporating additional T-cell receptor repertoires and functional annotations, including single-cell RNA sequencing analyses. This ongoing work aims to deepen our understanding of the functional roles of gamma-delta T cells in cancer and their interactions within the tumor microenvironment.

"This research not only expands our knowledge of gamma-delta T cells but also opens new avenues for therapeutic strategies," Wang said. "By understanding the specific roles of these cells in different cancers, we can better tailor treatments to improve patient outcomes."

The Immuno-Oncology Program and Biostatistics and Bioinformatics Shared Resources at Moffitt provided critical support and represent leading research expertise in computational immunology and personalized immunotherapy.

This study was supported by the National Institutes of Health (R01DE030493 and P20GM130454) and the National Cancer Institute (P30-CA076292).