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Caractérisation d’une signature sphingolipidique d’immunoéchappement dans le cancer du sein triple négatif

Abstract : Breast cancer, the most common malignancy affecting women, is responsible for the majority of woman death by cancer worldwide. There are three different breast cancer types defined by the expression of oestrogen and progesterone and HER2 receptors. The so-called triple negative breast cancer (TNBC), doesn’t express any of these receptors. Sphingolipid (SL) metabolism is frequently altered in breast cancer, alterations are associated with tumour progression. Although SL can act as immune response modulators in preclinical cancer models, there are, to date, no study assessing the impact of SL metabolism alterations on tumor development and associated immune response in Humans. In this setting, our aim was double. Our first objective was to characterize the SL signature in human mammary tumour biopsies from different pathological subtypes. Using high-resolution mass spectrometry assay, we identified elevated levels of C24:0-SL in TNBC, which could be used as potential biomarkers of this cancer subtype. Our second objective was to identify a SL signature associated with immune responses in breast cancer tissues. Tumour-infiltrating lymphocytes (TIL) were analyzed by flow cytometry and immunohistochemistry. Those analyses showed that, in TNBC, levels of C16:0-ceramide are positively correlated with the proportion CD8+ TIL and negatively correlated with that of FoxP3+ Treg TIL. In order to evaluate the potential influence of SL on the topology of infiltrating lymphocytes (intratumoural versus adjacent), we compared the SL levels in tumors depicting high or low proportions of intratumoral CD8+ T cells. We observed higher levels of sphingosine-1-phosphate (S1P) in low infiltrated intratumoral CD8+ T cells. Our observations suggest that C16:0-ceramide production could favor CD8+ T cell recruitment in TNBC, whereas S1P could act as an immune escape factor, negatively impacting on CD8+ TIL topology in mammary tumours. Our whole work indicates that a set of specific SL could constitute original biomarkers in TNBC. Moreover, reprogramming SL metabolism could improve (i) the infiltration of tumours by lymphocytes, both in terms of quality and quantity, and (ii) possibly, the efficacy of immunotherapy in breast cancer.
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Michaël Peres. Caractérisation d’une signature sphingolipidique d’immunoéchappement dans le cancer du sein triple négatif. Immunologie. Université Paul Sabatier - Toulouse III, 2018. Français. ⟨NNT : 2018TOU30337⟩. ⟨tel-02918110⟩

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