Prognostic Value of Fas/Fas Ligand Expression on Circulating Tumor Cells (CTCs) and Immune Cells in the Peripheral Blood of Patients with Metastatic Breast Cancer

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2024 Sep 14

PMID 39272785

Authors

Maria A Papadaki

Eleni Papadaki

Sofia Chatziavraam

Despoina Aggouraki

Kleita Michaelidou

Charalampos Fotsitzoudis

Maria Vassilakopoulou

Dimitrios Mavroudis

Sofia Agelaki

Affiliations

Soon will be listed here.

Abstract

The Fas/Fas ligand (FasL) system is a major apoptosis-regulating pathway with a key role in tumor immune surveillance and metastasis. The expression of Fas/FasL on mammary tumor tissues holds prognostic value for breast cancer (BC) patients. We herein assessed Fas/FasL expression on circulating tumor cells (CTCs) and matched peripheral blood mononuclear cells (PBMCs) from 98 patients with metastatic BC receiving first-line treatment. Fas+, FasL+, and Fas+/FasL+ CTCs were identified in 88.5%, 92.3%, and 84.6% of CTC-positive patients, respectively. In addition, Fas+/FasL+, Fas-/FasL+, and Fas-/FasL- PBMCs were identified in 70.3%, 24.2%, and 5.5% of patients, respectively. A reduced progression-free survival (PFS) was revealed among CTC-positive patients (median PFS: 9.5 versus 13.4 months; = 0.004), and specifically among those harboring Fas+/FasL+ CTCs (median PFS: 9.5 vs. 13.4 months; = 0.009). On the other hand, an increased overall survival (OS) was demonstrated among patients with Fas+/FasL+ PBMCs rather than those with Fas-/FasL+ and Fas-/FasL- PBMCs (median OS: 35.7 vs. 25.9 vs. 14.4 months, respectively; = 0.008). These data provide for the first time evidence on Fas/FasL expression on CTCs and PBMCs with significant prognostic value for patients with metastatic BC, thus highlighting the role of the Fas/FasL system in the peripheral immune response and metastatic progression of BC.

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References

Papadaki M, Mala A, Merodoulaki A, Vassilakopoulou M, Mavroudis D, Agelaki S . Investigating the Role of CTCs with Stem/EMT-like Features in Metastatic Breast Cancer Patients Treated with Eribulin Mesylate. Cancers (Basel). 2022; 14(16). PMC: 9405936. DOI: 10.3390/cancers14163903. View

Yamada A, Arakaki R, Saito M, Kudo Y, Ishimaru N . Dual Role of Fas/FasL-Mediated Signal in Peripheral Immune Tolerance. Front Immunol. 2017; 8:403. PMC: 5380675. DOI: 10.3389/fimmu.2017.00403. View

Guo Z, Zhang M, Tang H, Cao X . Fas signal links innate and adaptive immunity by promoting dendritic-cell secretion of CC and CXC chemokines. Blood. 2005; 106(6):2033-41. DOI: 10.1182/blood-2004-12-4831. View

Gonzalez H, Hagerling C, Werb Z . Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev. 2018; 32(19-20):1267-1284. PMC: 6169832. DOI: 10.1101/gad.314617.118. View

Yajima T, Hoshino K, Muranushi R, Mogi A, Onozato R, Yamaki E . Fas/FasL signaling is critical for the survival of exhausted antigen-specific CD8 T cells during tumor immune response. Mol Immunol. 2019; 107:97-105. DOI: 10.1016/j.molimm.2019.01.014. View

Ioachim H, Decuseara R, Giancotti F, Dorsett B . FAS and FAS-L expression by tumor cells and lymphocytes in breast carcinomas and their lymph node metastases. Pathol Res Pract. 2005; 200(11-12):743-51. DOI: 10.1016/j.prp.2004.09.006. View

OConnell J, Bennett M, OSullivan G, Collins J, Shanahan F . Fas counter-attack--the best form of tumor defense?. Nat Med. 1999; 5(3):267-8. DOI: 10.1038/6477. View

Suzuki I, Fink P . The dual functions of fas ligand in the regulation of peripheral CD8+ and CD4+ T cells. Proc Natl Acad Sci U S A. 2000; 97(4):1707-12. PMC: 26500. DOI: 10.1073/pnas.97.4.1707. View

Mullauer L, Mosberger I, Grusch M, Rudas M, Chott A . Fas ligand is expressed in normal breast epithelial cells and is frequently up-regulated in breast cancer. J Pathol. 2000; 190(1):20-30. DOI: 10.1002/(SICI)1096-9896(200001)190:1<20::AID-PATH497>3.0.CO;2-S. View

10.

Ta N, Chakrabandhu K, Huault S, Hueber A . The tyrosine phosphorylated pro-survival form of Fas intensifies the EGF-induced signal in colorectal cancer cells through the nuclear EGFR/STAT3-mediated pathway. Sci Rep. 2018; 8(1):12424. PMC: 6102278. DOI: 10.1038/s41598-018-30804-z. View

11.

Shinohara S, Takahashi Y, Komuro H, Matsui T, Sugita Y, Demachi-Okamura A . New evaluation of the tumor immune microenvironment of non-small cell lung cancer and its association with prognosis. J Immunother Cancer. 2022; 10(4). PMC: 8996063. DOI: 10.1136/jitc-2021-003765. View

12.

Peter M, Hadji A, Murmann A, Brockway S, Putzbach W, Pattanayak A . The role of CD95 and CD95 ligand in cancer. Cell Death Differ. 2015; 22(4):549-59. PMC: 4356349. DOI: 10.1038/cdd.2015.3. View

13.

Koshkina N, Yang Y, Kleinerman E . The Fas/FasL Signaling Pathway: Its Role in the Metastatic Process and as a Target for Treating Osteosarcoma Lung Metastases. Adv Exp Med Biol. 2020; 1258:177-187. DOI: 10.1007/978-3-030-43085-6_12. View

14.

Al Subeh Z, Poschel D, Redd P, Klement J, Merting A, Yang D . Lipid Nanoparticle Delivery of Fas Plasmid Restores Fas Expression to Suppress Melanoma Growth . ACS Nano. 2022; 16(8):12695-12710. PMC: 9721370. DOI: 10.1021/acsnano.2c04420. View

15.

Papadaki M, Monastirioti A, Apostolopoulou C, Aggouraki D, Papadaki C, Michaelidou K . TLR4 and pSTAT3 Expression on Circulating Tumor Cells (CTCs) and Immune Cells in the Peripheral Blood of Breast Cancer Patients: Prognostic Implications. Cancers (Basel). 2022; 14(4). PMC: 8869985. DOI: 10.3390/cancers14041053. View

16.

Husain N, Chiocca E, Rainov N, Louis D, Zervas N . Co-expression of Fas and Fas ligand in malignant glial tumors and cell lines. Acta Neuropathol. 1998; 95(3):287-90. DOI: 10.1007/s004010050799. View

17.

Levoin N, Jean M, Legembre P . CD95 Structure, Aggregation and Cell Signaling. Front Cell Dev Biol. 2020; 8:314. PMC: 7214685. DOI: 10.3389/fcell.2020.00314. View

18.

Muschen M, Moers C, Warskulat U, Even J, Niederacher D, Beckmann M . CD95 ligand expression as a mechanism of immune escape in breast cancer. Immunology. 2000; 99(1):69-77. PMC: 2327134. DOI: 10.1046/j.1365-2567.2000.00921.x. View

19.

Nagata S, Golstein P . The Fas death factor. Science. 1995; 267(5203):1449-56. DOI: 10.1126/science.7533326. View

20.

Maffuid K, Cao Y . Decoding the Complexity of Immune-Cancer Cell Interactions: Empowering the Future of Cancer Immunotherapy. Cancers (Basel). 2023; 15(16). PMC: 10453128. DOI: 10.3390/cancers15164188. View