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Autophagy. 2016 May 3;12(5):864-75. doi: 10.1080/15548627.2016.1154244. Epub 2016 Mar 16.

The presence of LC3B puncta and HMGB1 expression in malignant cells correlate with the immune infiltrate in breast cancer.

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a Department of Medical Oncology , Georges François Leclerc Center , Dijon , France.
b Institut National de la Santé et de la Recherche Médicale, Avenir Team INSERM, CRI-866 University of Burgundy , Dijon , France.
c Institut National de la Santé et de la Recherche Médicale, U1015, Equipe labellisée Ligue Nationale Contre le Cancer, Institut Gustave Roussy , Villejuif , France.
d Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus , Villejuif , France.
e Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers , Paris , France.
f INSERM, U1138 , Paris , France.
g Université Paris Descartes, Sorbonne Paris Cité , Paris , France.
h University of Paris Sud XI , Villejuif , France.
i Center of Clinical Investigations in Biotherapies of Cancer (CICBT) , Villejuif , France.
j Center Jean Perrin, EA 4677 Clermont-Ferrand , Clermont-Ferrand , France.
k ERTICa, EA 4677 University of Auvergne , Clermont-Ferrand , France.
l Department of Pathology and Tumor Biology , Georges François Leclerc Center , Dijon , France.
m Biostatistics and Epidemiology Unit, EA 4184, Centre Georges Francois Leclerc Dijon , France.
n Department of Medical Oncology and Breast Cancer Group , Institut Gustave Roussy , Villejuif , France.
o INSERM U981 Identification of molecular predictors and new targets for cancer treatment , Institut Gustave Roussy , Villejuif , France.
p Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris , Paris , France.
q Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital , Stockholm , Sweden.


Several cell-intrinsic alterations have poor prognostic features in human breast cancer, as exemplified by the absence of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β)-positive puncta in the cytoplasm (which indicates reduced autophagic flux) or the loss of nuclear HMGB1 expression by malignant cells. It is well established that breast cancer is under strong immunosurveillance, as reflected by the fact that scarce infiltration of the malignant lesion by CD8(+) cytotoxic T lymphocytes or comparatively dense infiltration by immunosuppressive cell types (such as FOXP3(+) regulatory T cells or CD68(+) tumor-associated macrophages), resulting in low CD8(+):FOXP3(+) or CD8(+):CD68(+) ratios, has a negative prognostic impact. Here, we reveal the surprising finding that cell-intrinsic features may influence the composition of the immune infiltrate in human breast cancer. Thus, the absence of LC3B puncta is correlated with intratumoral (but not peritumoral) infiltration by fewer CD8(+) cells and more FOXP3(+) or CD68(+) cells, resulting in a major drop in the CD8(+):FOXP3(+) or CD8(+):CD68(+) ratios. Moreover, absence of HMGB1 expression in nuclei correlated with a general drop in all immune effectors, in particular FOXP3(+) and CD68(+) cells, both within the tumor and close to it. Combined analysis of LC3B puncta and HMGB1 expression allowed for improved stratification of patients with respect to the characteristics of their immune infiltrate as well as overall and metastasis-free survival. It can be speculated that blocked autophagy in, or HMGB1 loss from, cancer cells may favor tumor progression due to their negative impact on anticancer immunosurveillance.


CD8; HMGB1; LC3; Treg cells; autophagy; breast cancer; histology; lymphocytes; macrophages; pathology; prognostic

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