Abstract
ABSTRACTSeveral 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.
Highlights
The relationship between autophagy and cancer is complex and possibly context-dependent.[1]
MAP1LC3B/LC3B has no major impact on patient survival,[7] the absence of LC3B puncta, which correlates with increased levels of the autophagy receptor SQSTM1/p62 and indicates a reduction of autophagic flux, has a negative prognostic impact, as we have reported on 2 cohorts comprising approximately
Autophagy-deficient carcinomas and melanomas developing in immunocompetent mice fail to attract immune effects upon treatment by chemotherapy or radiotherapy, correlating with markedly reduced treatment responses.[16,18,19,20]. Intrigued by this putative link between autophagy and immunosurveillance, which is suggested by experiments in mice, we decided to investigate the possible relationship between autophagy and the immune infiltrate in human breast cancer, a pathology that is under strong immunosurveillance
Summary
The relationship between autophagy and cancer is complex and possibly context-dependent.[1]. Autophagy-deficient colorectal cancers and lung adenocarcinomas fail to elicit protective anticancer immune responses when they are used as vaccines subsequent to their in vitro stimulation with anthracyclines or oxaliplatine.[18] Autophagy-deficient carcinomas and melanomas developing in immunocompetent mice fail to attract immune effects upon treatment by chemotherapy or radiotherapy, correlating with markedly reduced treatment responses.[16,18,19,20] Intrigued by this putative link between autophagy and immunosurveillance, which is suggested by experiments in mice, we decided to investigate the possible relationship between autophagy and the immune infiltrate in human breast cancer, a pathology that is under strong immunosurveillance. Our results plead in favor of a major influence of the intracellular milieu within cancer cells on the immunosurveillance system
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