Search

Cancer immunosurveillance generally relies on adaptive immune programs executed by CD8+ T cells. Our findings demonstrate that CD8+ T cells fail to control early oncogenesis in a mouse model of luminal B breast cancer and suggest that natural killer (NK) cells may instead play a predominant role in this setting. [ABSTRACT FROM AUTHOR]

The treatment of breast cancer largely depends on the utilization of immunogenic chemotherapeutics, which, as a common leitmotif, stimulate the exposure of calreticulin (CALR) on the surface of cancer cells, thereby facilitating their recognition by dendritic cells for the uptake of tumor-associated antigens and subsequent antigen cross-presentation to cytotoxic T cells. Breast cancer cells also express the calreticulin antagonist CD47, which inhibits tumor cell phagocytosis and consequently subverts anticancer immune responses. Here, we treated carcinogen-induced or transplantable mouse models of cancer by a CD47 blocking antibody that was at least as efficient as chemotherapy and that could be favorably combined with the anthracycline mitoxantrone in the context of carcinogen-induced orthotopic breast cancers. Monotherapy by CD47 blockade led to a reduction in tumor growth and an increase in overall survival. Of note, this treatment lead to a moderate depletion of M2 macrophages as well as close-to-complete elimination of regulatory T cells from the tumor bed, suggesting a strong favorable impact of CD47 blockade on the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Summary Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed. [ABSTRACT FROM AUTHOR]

The biological roles of estrogen receptor 1 (ERS1), estrogen receptor 2 (ERS2), and aromatase (CYP19A1) genes in the development of non-small cell lung cancer (NSCLC) is unclear, as is the use of their expression as a prognostic factor. The aim of this study was to investigate the prognostic value of estrogen receptors and aromatase mRNA expression, along with aromatase protein concentration, in resected NSCLC patients. Tumor and non-tumor lung tissue samples were analyzed for the mRNA expression of ERS1, ERS2 and CYP19A1 by RT-PCR. Aromatase concentration was measured with an ELISA. A total of 96 patients were included. ERS1 expression was significantly higher in non-tumor tissue than in tumor samples. Two gene expression categories were created for each gene (and protein): high and low. ERS1 high category showed increased overall survival (OS) when compared to the low expression category. Aromatase protein concentration was significantly higher in tumor samples. Higher ERS1 expression in tumor tissues was related to longer overall survival. The analysis of gene expression combinations provides evidence for longer OS when both ERS1 and ERS2 are highly expressed. ESR1, alone or in combination with ERS2 or CYP19A1, is the most determining prognostic factor within the analyzed 3 genes. It seems that ERS1 can play a role in NSCLC prognosis, alone or in combination with other genes such as ERS2 or Cyp19a1. ERS2 in combination with aromatase concentration could have a similar function. [ABSTRACT FROM AUTHOR]

In a series of 248 tumor samples obtained from image-guided biopsies from patients diagnosed with ductal carcinomain situof the breast, we attempted to identify biomarkers that predict microinfiltration at definitive surgery or relapse during follow-up. For this, we used immunohistochemical methods, followed by automated image analyses, to measure the mean diameter of nuclei (which correlates with ploidy), the phosphorylation of eukaryotic initiation factor 2α (eIF2α, which reflects endoplasmic reticulum stress) as well as the density and ratio of CD8+cytotoxic T lymphocytes and FOXP3+regulatory T cells. The median nuclear diameter of malignant cells correlated with eIF2α phosphorylation (in cancerous tissue), which in turn correlated with the density of the CD8+infiltrate and the CD8+/FOXP3 ratio (both in cancerous and the adjacent non-cancerous parenchyma). Neither microinfiltration nor lymph node involvement was associated with the probability of relapse. Both correlated positively with the CD8+/FOXP3 ratio in the malignant area. In contrast, relapse was associated with a paucity of the CD8+infiltrate as well as an unfavorable CD8+/FOXP3 ratio, both in malignant and non-malignant parenchyma. The combined analysis of the CD8+/FOXP3 ratio in cancerous and non-cancerous tissues revealed a significant impact of their interaction on the probability of relapse, but not on the presence of microinfiltration or lymph node metastasis. Altogether, these results support the idea of an immunosurveillance system that determines the risk of relapse in ductal carcinomain situof the breast. [ABSTRACT FROM PUBLISHER]