Autophagic Markers in Chordomas: Immunohistochemical Analysis and Comparison with the Immune Microenvironment of Chordoma Tissues.

Georgia Karpathiou,Cédric Barrey,Timothée Jacquesson,Jean Michel Prades,Jean Marc Dumollard,Lila Krebs-Drouot,François Vassal,David Meyronet,Emmanuel Jouanneau,Maroa Dridi,Michel Péoc’H,Jean Boutonnat

doi:10.3390/cancers13092169

Abstract

Simple SummaryIn contrast to normal notochords, autophagic factors are often present in chordomas. Furthermore, PD-L1+ immune cells also express LC3B, suggesting the need for further investigations between autophagy and the immune microenvironment.Chordomas are notably resistant to chemotherapy. One of the cytoprotective mechanisms implicated in chemoresistance is autophagy. There are indirect data that autophagy could be implicated in chordomas, but its presence has not been studied in chordoma tissues. Sixty-one (61) chordomas were immunohistochemically studied for autophagic markers and their expression was compared with the expression in notochords, clinicopathological data, as well as the tumor immune microenvironment. All chordomas strongly and diffusely expressed cytoplasmic p62 (sequestosome 1, SQSTM1/p62), whereas 16 (26.2%) tumors also showed nuclear p62 expression. LC3B (Microtubule-associated protein 1A/1B-light chain 3B) tumor cell expression was found in 44 (72.1%) tumors. Autophagy-related 16‑like 1 (ATG16L1) was also expressed by most tumors. All tumors expressed mannose-6-phosphate/insulin-like growth factor 2 receptor (M6PR/IGF2R). LC3B tumor cell expression was negatively associated with tumor size, while no other parameters, such as age, sex, localization, or survival, were associated with the immunohistochemical factors studied. LC3B immune cell expression showed a significant positive association with programmed death-ligand 1 (PD-L1)+ immune cells and with a higher vascular density. ATG16L1 expression was also positively associated with higher vascular density. Notochords (n = 5) showed different immunostaining with a very weak LC3B and M6PR expression, and no p62 expression. In contrast to normal notochords, autophagic factors such as LC3B and ATG16L1 are often present in chordomas, associated with a strong and diffuse expression of p62, suggesting a blocked autophagic flow. Furthermore, PD-L1+ immune cells also express LC3B, suggesting the need for further investigations between autophagy and the immune microenvironment.

Highlights

Chordomas are rare bone tumors, accounting for 1.4% of primary bone malignancies and showing a median overall survival of 7 years; they are assumed to derive from notochordal remnants probably driven by brachyury activation [1]
One mechanism that tumor cells use to survive during adverse conditions is autophagy [3], the discovery of which led to a 2016 Nobel Prize award for Yoshinori Ohsumi [4]
We found that LC3B tumor cell expression (χ2 test) was negatively associated with tumor size (p = 0.03, χ2 = 4.5), where tumor size was available for 29 tumors and the median tumor size (43 mm) was used as the cut-off value for the χ2 test

Summary

Introduction

Chordomas are rare bone tumors, accounting for 1.4% of primary bone malignancies and showing a median overall survival of 7 years; they are assumed to derive from notochordal remnants probably driven by brachyury activation [1] These malignant tumors, primarily treated with surgery and/or radiotherapy, are notably resistant to chemotherapy [2]. One mechanism that tumor cells use to survive during adverse conditions is autophagy [3], the discovery of which led to a 2016 Nobel Prize award for Yoshinori Ohsumi [4] It is a process characterized by the formation of vesicles, autophagosomes, engulfing cellular constituents and leading them to degradation and recycling by fusion with the lysosomes [3]. Despite this indirect evidence of chordomas association with autophagy, to the best of our knowledge, the presence of this mechanism has never been studied in chordoma tissues

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