Solid stress impairs lymphocyte infiltration into lymph-node metastases.

Area of Science:

• Immunology
• Oncology
• Pathology

Background:

• Effective anticancer immune responses rely on T cells within lymph nodes.
• Tumor cells can metastasize to lymph nodes, hindering immune surveillance and promoting cancer progression.
• Lymphocyte infiltration into metastatic lymph node lesions is crucial for anti-tumor immunity.

Purpose of the Study:

• To investigate the mechanisms limiting lymphocyte infiltration into lymph node metastases.
• To determine the role of solid stress in lymphocyte exclusion from nodal tumors.
• To explore therapeutic strategies for enhancing lymphocyte entry into metastatic lesions.

Main Methods:

• Analysis of patient tissues (breast, colon, head and neck cancers) and mouse models of breast cancer lymph node metastasis.
• Assessment of lymphocyte presence and high endothelial venule (HEV) function in relation to solid stress within lymph node lesions.
• Experimental manipulation to relieve solid stress in mice and quantify subsequent lymphocyte infiltration.

Main Results:

• Lymphocytes were found to be excluded from metastatic lesions within lymph nodes in both human cancer patients and mouse models.
• Solid stress, generated by metastatic lesion growth, was identified as a key factor causing lymphocyte exclusion.
• Solid stress led to a reduction in functional high endothelial venules, impeding lymphocyte entry.
• Alleviating solid stress in mice increased lymphocyte presence in lymph node lesions approximately 15-fold.

Conclusions:

• Solid stress within lymph node metastases creates a physical barrier to lymphocyte infiltration.
• This mechanism contributes to immune evasion in lymph node metastasis.
• Targeting and relieving solid stress presents a promising therapeutic strategy to enhance T-cell infiltration and improve immunotherapy efficacy against metastatic cancer.