Thymic Microenvironment Remodeling in Cancer Cachexia as a Determinant of Checkpoint Inhibitor Efficacy and Toxicity

Area of Science:

• Immunology
• Oncology
• Cancer Biology

Background:

• Immune checkpoints link autoimmunity and cancer.
• Thymus atrophy is linked to autoimmune inflammation.
• The effect of cancer cachexia on thymic involution and its clinical significance is not well understood.

Purpose of the Study:

• Investigate the impact of cancer cachexia on thymic involution.
• Determine the clinical significance of cachexia-induced thymic changes.
• Explore the association with immune checkpoint inhibitor (ICI) treatment efficacy.

Main Methods:

• Single-cell sequencing, immunofluorescence, and flow cytometry in orthotopic hepatocellular cancer (HCC) mice with cachexia.
• Analysis of thymic changes in cachectic HCC mouse models.
• Follow-up study of cancer patients receiving anti-PD-1/L1 antibody treatment to correlate serum autoantibodies with ICI efficacy.

Main Results:

• Cachexia in HCC mice caused thymic fibroblast immaturity, impaired antigen processing, and reduced interaction with thymocytes.
• Cachectic mice showed thymic medulla degradation and altered fibroblast gene expression, suggesting impaired T cell negative selection.
• Cancer cachexic erythroid progenitor cells induced progenitor cell death and reduced specific medullary fibroblasts; elevated autoantibodies were observed in cachectic mice and ICI-treated patients, correlating with treatment outcomes.

Conclusions:

• Cancer cachexia disrupts medullary fibroblast maturity, impairing T cell negative selection and expanding T cell receptor repertoire against tissue-restricted antigens.
• These cachexia-induced thymic alterations may mediate both adverse and favorable effects of ICIs in cancer therapy.