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ABSTRACT
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.
Abbreviations
| AGER | = | advanced glycosylation end product-specific receptor |
| ATG7 | = | autophagy-related 7 |
| ATG10 | = | autophagy-related 10 |
| ATG12 | = | autophagy-related 12 |
| ATG5, | = | autophagy-related 7 |
| ATP | = | adenosine tri-phosphate |
| BC, | = | breast cancer |
| BECN1 | = | Beclin 1 autophagy related |
| CD68, | = | cluster of differentiation 68 |
| CD8, | = | cluster of differentiation 8 |
| CTL, | = | cytotoxic T lymphocyte |
| EDTA | = | ethylenediaminetetraacetic acid |
| ENTPD1 | = | ectonucleoside triphosphate diphosphohydrolase 1 |
| FFPE | = | formalin-fixed paraffin-embedded |
| FOXP3 | = | forkhead box P3 |
| HMGB1 | = | high mobility group box 1 |
| KRAS | = | Kirsten rat sarcoma viral oncogene homolog |
| MAP1LC3B/LC3B | = | microtubule-associated protein 1 light chain 3 β |
| MFS | = | metastasis free survival |
| mRNA | = | messenger ribonucleic acid |
| OS, | = | overall survival |
| PBS, | = | phosphate-buffered saline |
| SQSTM1/p62 | = | sequestosome 1 |
| TAM | = | tumor-associated macrophage |
| TIL, | = | tumor-infiltrating lymphocyte |
| TLR4 | = | toll like receptor 4 |
| WNT1 | = | wingless-type MMTV integration site family member 1 |
Disclosure of potential conflicts of interest
None of the authors needed to declare a conflict of interest.
Acknowledgments
The authors would like to thank Mrs S Piterboth, and Pr J-Y. Scoazec from the Department of Biology and Pathology of Gustave Roussy Institute (Villejuif) for their help in immunostaining.
Funding
GK and LZ are supported by the Ligue contre le Cancer (équipes labelisées); Agence Nationale de la Recherche (ANR); Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC for GK); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). LZ was supported by ISREC and Swiss Bridge Foundation.