Failed immune responses across multiple pathologies share pan-tumor and circulating lymphocytic targets

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Tumor-infiltrating lymphocytes (TILs) are linked to better outcomes but can signal a systemic immune failure against cancer.
• Cancer immunotherapies aim to reverse TIL tolerance while maintaining anti-tumor reactivity and neoantigen specificity.

Purpose of the Study:

• To identify common gene signatures in circulating and tumor-infiltrating lymphocytes in clear cell renal cell carcinoma.
• To validate modulated genes associated with disease outcomes across multiple cancer types.

Main Methods:

• Comprehensive transcriptomic analyses were performed.
• Bioinformatic approaches were used to identify gene signatures and validate their association with disease outcomes.

Main Results:

• Three genes (LEF1, FASLG, MMP9) in circulating lymphocytes effectively distinguished cancer patients from healthy controls.
• These genes are associated with resistance to cancer immunotherapies and infections, suggesting pan-cancer and pan-pathology immune failure profiles.
• A lymphocytic matrix metallopeptidase cell migration pathway correlates with multi-cancer recurrence and suggests a non-invasive diagnostic approach.

Conclusions:

• Identified non-invasive, differentially expressed genes show potential for precision diagnostics.
• These findings support the development of precision immunotherapeutics targeting systemic immune response failures across various diseases.