Store-Operated Ca²⁺ Entry Is Up-Regulated in Tumour-Infiltrating Lymphocytes from Metastatic Colorectal Cancer...

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• Store-operated calcium entry (SOCE) is crucial for cytotoxic T lymphocyte (CTL) anti-cancer activity.
• Enhanced SOCE in cancer cells is linked to increased STIM1 and Orai1 expression/function.
• This study investigates SOCE in tumor-infiltrating lymphocytes (TILs) from metastatic colorectal cancer (mCRC) patients.

Purpose of the Study:

• To evaluate SOCE expression and function in TILs from mCRC patients.
• To understand the mechanisms underlying enhanced SOCE in TILs.
• To assess the impact of modulating SOCE on TIL cytotoxic activity.

Main Methods:

• Functional studies using ex vivo expanded TILs from CRC liver metastases.
• Comparison with peripheral blood T cells from healthy donors (hPBTs) and mCRC patients (cPBTs).
• Pharmacological manipulation of SOCE pathways and assessment of Ca2+ responses and cytotoxic activity.

Main Results:

• SOCE amplitude is significantly enhanced in TILs compared to controls.
• STIM1 protein is upregulated specifically in TILs.
• Enhanced SOCE is primarily modulated by diacylglycerol kinase, preventing protein kinase C inhibition.
• Increased SOCE leads to a stronger Ca2+ response upon T-cell receptor stimulation by autologous mCRC cells.
• Pharmacological reduction of Ca2+ influx with BTP-2 enhances cytotoxic activity at low target:effector ratios.

Conclusions:

• SOCE is demonstrably enhanced in ex vivo-expanded TILs from mCRC patients.
• Decreasing Ca2+ influx via SOCE inhibition (using BTP-2) augments cytotoxic activity, particularly at lower TIL densities.