IL-33-activated ILC2s induce tertiary lymphoid structures in pancreatic cancer

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Tertiary lymphoid structures (TLSs) are crucial for immune responses in inflamed tissues like tumors.
• The precise triggers and cellular mechanisms initiating TLS formation via the lymphotoxin (LT)-LTβ receptor (LTβR) pathway are not fully understood.

Purpose of the Study:

• To identify the inflammatory signals and cells responsible for inducing TLS formation.
• To investigate the role of interleukin-33 (IL-33) in TLS induction and tertiary lympho-organogenesis.
• To explore the therapeutic potential of targeting the IL-33 pathway in pancreatic ductal adenocarcinoma (PDAC).

Main Methods:

• Utilized mouse models of colitis and PDAC to study TLS formation.
• Investigated the function of IL-33 using Il33-deficient mice.
• Analyzed the activation of group 2 innate lymphoid cells (ILC2s) by IL-33 and their role in tertiary lympho-organogenesis.
• Examined human PDAC tissues for the presence of ILC2s and IL-33-expressing cells.
• Engineered a recombinant human IL-33 protein for therapeutic intervention in mouse models.

Main Results:

• IL-33 deficiency significantly reduced inflammation- and LTβR-induced TLSs in colitis and PDAC models.
• In PDAC, IL-33 activates ILC2s, which engage myeloid cells to initiate TLS formation.
• Lympho-organogenic ILC2s can migrate from the gut to PDAC and are influenced by gut microbiota.
• Presence of ILC2s and IL-33-expressing cells in human PDAC TLSs correlates with better prognosis.
• Engineered IL-33 protein enhanced intratumoral ILC2s and TLSs, improving anti-tumor activity in PDAC mice.

Conclusions:

• Identified IL-33 as a key inducer of TLSs, acting through ILC2s and myeloid cells.
• Revealed a druggable pathway involving alarmins and ILC2s for inducing TLSs in inflammation and cancer.
• Demonstrated the therapeutic potential of IL-33-based immunotherapy for PDAC by promoting lympho-organogenesis.