title: Biomarkers of immunogenic stress in metastases from melanoma patients: Correlations with the immune infiltrate.
abstract: Melanoma is known to be under latent immunosurveillance. Here, we studied four biomarkers of immunogenic cell stress and death (microtubule-associated proteins 1A/1B light chain 3B (MAP-LC3B, best known as LC3B)-positive puncta in the cytoplasm as a sign of autophagy; presence of nuclear HMGB1; phosphorylation of eIF2α; increase in ploidy) in melanoma cells, in tissue microarrays (TMA) from metastases from 147 melanoma patients. These biomarkers of immunogenicity were correlated with the density of immune cells infiltrating the metastases and expressing CD3, CD4(+), CD8(+), CD20, CD45, CD56, CD138, CD163, DC-LAMP or FOXP3. LC3B puncta positively correlated with the infiltration of metastases by CD163(+) macrophages, while expression of HMGB1 correlated with infiltration by FOXP3(+) regulatory T cells and CD56(+) lymphocytes. eIF2α phosphorylation was associated with an augmentation of nuclear diameters, reflecting an increase in ploidy. Interestingly, therapeutic vaccination led to a reduction of eIF2α phosphorylation suggestive of immunoselection against cells bearing this sign of endoplasmic reticulum (ER) stress. None of the stress/death-related biomarkers had a significant prognostic impact, contrasting with the major prognostic effect of the ratio of cytotoxic T lymphocytes (CTL) over immunosuppressive FOXP3(+) and CD163(+) cells. Altogether, these results support the idea of a mutual dialog between, on one hand, melanoma cells with their cell-intrinsic stress pathways and, on the other hand, immune effectors. Future work is required to understand the detailed mechanisms of this interaction.
authors.affiliation: Department of Medical Oncology, Georges François Leclerc Center, Dijon, France; Institut National de la Santé et de la Recherche Médicale, Avenir Team INSERM, University of Burgundy, Dijon, France; Institut National de la Santé et de la Recherche Médicale, U1015, Equipe labellisée Ligue Nationale Contre le Cancer, Institut Gustave Roussy, Villejuif, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Ladoire
authors.affiliation: Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM, U1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; University of Paris Sud XI, Villejuif, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Senovilla
authors.affiliation: Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus , Villejuif, France.
authors.forename: David
authors.initials: D
authors.lastname: Enot
authors.affiliation: Department of Medical Oncology, Georges François Leclerc Center, Dijon, France; Institut National de la Santé et de la Recherche Médicale, Avenir Team INSERM, University of Burgundy, Dijon, France.
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1015, Equipe labellisée Ligue Nationale Contre le Cancer, Institut Gustave Roussy , Villejuif, France.
authors.forename: Vichnou
authors.initials: V
authors.lastname: Poirier-Colame
authors.affiliation: Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM, U1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Kariman
authors.initials: K
authors.lastname: Chaba
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA, USA; Department of Surgery, University of Virginia, Charlottesville, VA, USA.
authors.forename: Gulsun
authors.initials: G
authors.lastname: Erdag
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA, USA; Department of Surgery, University of Virginia, Charlottesville, VA, USA.
authors.forename: Jochen T
authors.initials: JT
authors.lastname: Schaefer
authors.affiliation: Department of Surgery, University of Virginia , Charlottesville, VA, USA.
authors.forename: Donna H
authors.initials: DH
authors.lastname: Deacon
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U1015, Equipe labellisée Ligue Nationale Contre le Cancer, Institut Gustave Roussy, Villejuif, France; University of Paris Sud XI, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.affiliation: Department of Surgery, University of Virginia , Charlottesville, VA, USA.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Slingluff
authors.affiliation: Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM, U1138, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
keywords: Autophagy; HMGB1; LC3; immune infiltrates; immunogenic cell death; melanoma