PhD Scientific Days 2025

Pathological and Oncological Sciences III.

A potential immune escape mechanism mediated by LPA in human melanoma

Előadó neve

Major Enikő, PhD

Neptun code

IG9PPT

Előadó munkahelye

Institute of Translational Medicine, Semmelweis University

Előadó telefonszáma

+36305342593

Előadó e-mail címe

majoreniko94@gmail.com

Az előadás címe

A potential immune escape mechanism mediated by LPA in human melanoma

Szerző(k) neve és munkahelye

Enikő Major¹, Kuan-Hung Lin², Sue-Chin Lee², Krisztina Káldi³, Balázs Győrffy⁴, Gábor Tigyi², Zoltán Benyó¹

1: Institute of Translational Medicine, Semmelweis University
2: Department of Physiology, University of Tennessee Health Science Centre, Memphis, TN, USA
3: Department of Physiology, Semmelweis University
4: Department of Bioinformatics, Semmelweis University

Bemutatás módja

Szóbeli

Szekció

Pathological and Oncological Sciences III.

Language of the presentation

English

Preferred session

Pathological and Oncological Sciences

Összefoglaló szövege

While immune checkpoint inhibitors (ICIs) revolutionized the treatment of metastatic melanoma, providing improved progression-free survival, approximately 50% of the patients do not respond favorably to them. Low expression of human leukocyte antigen-DR (HLA-DR) is associated with poor prognosis and reduced responsiveness to ICIs. Lysophosphatidic acid (LPA) is a bioactive lipid mediator produced in large amounts by melanoma and is presented abundantly in the tumor microenvironment. LPA regulates the release of various cytokines and chemokines from tumor cells, influencing cancer progression, metastasis, and tumor immunity. In the present study, we aimed to investigate the potential role of LPA-induced cytokine release in regulating HLA-DR expression and clarify the underlying signaling mechanisms in human melanoma cells. For analyzing LPA-mediated signaling pathways in A375 and A2058 human melanoma cells, pharmacological inhibitors (PTX, AM095, Ki16425), siRNAs (NF-κB1, DR6, IL-10), and neutralizing antibodies (anti-IL-10, IgG1) were used. Gene expression was followed by qPCR, cytokine release was detected by ELISA, and cell surface protein expression was measured by flow cytometry. We found that LPA suppresses HLA-DR expression in human melanoma cells by upregulating the expression of death receptor 6 (DR6). DR6 is inducibly expressed in tumor cells and regulates diverse cellular functions, including cytokine release. Our results demonstrate that stimulation of the Gi-coupled LPAR1 by LPA increases DR6 expression via activation of NF-κB1 in human melanoma cells. Subsequently, LPA upregulates the expression and release of interleukin 10 (IL-10) via the LPAR1-DR6 axis, resulting in diminished expression of HLA-DR. Analyzing transcriptome databases of melanoma tissue samples revealed a statistically significant correlation between the expression of LPAR1, DR6, and IL-10 and an association between increased expression of LPAR1 and reduced effectiveness of ICI. Taken together, our results indicate that the LPAR1-DR6-IL-10 autocrine signaling loop could constitute a novel mechanism used by tumor cells to evade immunosurveillance, providing a potential target in ICI therapy resistance of melanoma. This study was supported by NKFIH K-125174, K-132393, K-135683, 2020-1.1.6-JÖVŐ-2021-00010, TKP2021-EGA-25, EFOP-3.6.3-VEKOP-16-2017-00009 grants, EKÖP-2024-173.

University

Semmelweis University

Supervisor

Zoltán Benyó

Publication of my abstract

I do not give consent to the publication of my abstract on the website of the congress.

phd.section.field

after finishing doctoral studies with absolutorium (PhD)

Kind

Szabad

Status

elfogadva

Accepted presentation method

szóbeli

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

7454

Start

17:30

End

17:45