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

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 b)-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 C cytotoxic T lymphocytes or comparatively dense infiltration by immunosuppressive cell types (such as FOXP3 C regulatory T cells or CD68C tumor-associated macrophages), resulting in low CD8C 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 CD8C cells and more FOXP3C or CD68 C cells, resulting in a major drop in the CD8 C :FOXP3 C or CD8 C :CD68 C ratios. Moreover, absence of HMGB1 expression in nuclei correlated with a general drop in all immune effectors, in particular FOXP3C and CD68 C 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.

Positive impact of autophagy in human breast cancer cells on local immunosurveillance

“…1). 10 Altogether, these results support that the aforementioned results obtained in mouse models can be extrapolated to human malignancies (or at least to human breast cancer). It should be noted that high expression of CD39 and that of another ectoenzyme, CD73, which operates downstream of CD39 to generate adenosine, also constitutes a negative prognostic marker in breast cancer, 9 suggesting that the entire molecular cascade (deficient autophagy reduced ATP release and increase conversion of ATP into adenosine adenosinergic receptor-dependent recruitment of Tregs failing immunosurveillance) delineated in mice might apply to mammary carcinoma as well.…”

Systemic autophagy in the therapeutic response to anthracycline-based chemotherapy

“…30 In the context of cancer, autophagy induction may have oncopreventive and improve therapeutic outcome after chemotherapy effects. 18,19,31–33 In addition, starvation, which is one of the best-known inducers of autophagy, increases the resistance of mice against the toxic effects of anthracycline-based chemotherapy at the same time that it improves tumor growth reduction. 20,34 This autophagy- or starvation-mediated improvement of chemotherapeutic responses has been attributed to an increase in anticancer immunity.…”

The ratio of CD8+/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ

“…[1][2][3][4][5][6][7] This applies to the composition of the immune infiltrate at diagnosis, [1][2][3][4]8,9 as well as for the dynamic changes induced by anthracycline-based chemotherapy, in which an amelioration of the ratio of CD8…”