Role of immune-checkpoint LAG3 as a biomarker finding tool in patient-derived organoid cultures of breast cancer

被引：1

作者：

Carrese, Barbara ^{[1
]}

Coppola, Luigi ^{[1
]}

Smaldone, Giovanni ^{[1
]}

D'Aiuto, Massimiliano ^{[2
]}

Mossetti, Gennaro ^{[3
]}

Febbraro, Antonio ^{[4
]}

Soricelli, Andrea ^{[1
]}

Salvatore, Marco ^{[1
]}

Ciaramella, Vincenza ^{[1
]}

机构：

[1] IRCCS SYNLAB SDN, I-80143 Naples, Italy

[2] Clin Villa Fiorita, I-81031 Aversa, Italy

[3] Maria Rosaria Clin, Pathol Anat Serv, I-80045 Naples, Italy

[4] Casa Cura Cobellis, Oncol Unit, Vallo Della Lucania, Italy

来源：

SCIENTIFIC REPORTS | 2024年 / 14卷 / 01期

关键词：

Breast cancer; Organoids; LAG3; Biomarkers; Immune micro-environment;

D O I：

10.1038/s41598-024-83061-8

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

LAG3 plays a regulatory role in immunity and emerged as an inhibitory immune checkpoint molecule comparable to PD-L1 and CTLA-4 and a potential target for enhancing anti-cancer immune responses. We generated 3D cancer cultures as a model to identify novel molecular biomarkers for the selection of patients suitable for alpha-LAG3 treatment and simultaneously the possibility to perform an early diagnosis due to its higher presence in breast cancer, also to achieve a theragnostic approach. Our data confirm the extreme dysregulation of LAG3 in breast cancer with significantly higher expression in tumor tissue specimens, compared to non-cancerous tissue controls. LAG3 blockade inhibited proliferation of in vitro and ex vivo 3D human organoids and immune micro-environment through both a decrease of PD-L1, TIM-3 and CTLA4 expression and an increased production of several pro-inflammatory cytokines (IFN gamma, IL-12, IL-6, IL-1 beta, TNF alpha) and EMT markers. These effects trigger a more permissive anti-tumor immune reaction, recruiting immune cells to the tumor sites, boosting the anti-tumor response. LAG3 acts as an immunosuppressive molecule in breast cancer, inhibiting T CD8 + cell proliferation and cytokine production by T cells. We proposed the modulation of a novel checkpoint molecule, such as LAG3, as potential biomarkers associated to a rapid diagnosis.

引用

页数：10

共 22 条

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