空间蛋白质组学揭示 sirtuin 1 是人类黑色素瘤 T 细胞浸润的决定因素

The tumour microenvironment significantly influences the clinical response of patients to therapeutic immune checkpoint inhibition (ICI), but a comprehensive understanding of the underlying immune-regulatory proteome is still lacking.

To decipher targetable biologic processes that determine tumour-infiltrating lymphocytes (TiLs) as a cellular equivalent of clinical response to ICI.

We mapped the spatial distribution of proteins in TiL-enriched vs. TiL-low compartments in melanoma by combining microscopy, matrix-assisted laser desorption mass spectrometry imaging and liquid chromatography-mass spectrometry, as well as computational data mining. Pharmacological modulation of sirtuin 1 (SIRT1) activity in syngeneic mouse models was used to evaluate the efficacy of pharmacological SIRT1 activation in two syngeneic melanoma mouse models, one known to be -programmed cell death protein 1 (PD-1) sensitive and the other -PD-1 resistant.

Spatial proteomics and gene ontology-based enrichment analysis identified > 145 proteins enriched in CD8high tumour compartments, including negative regulators of mammalian target of rapamycin signalling such as SIRT1. Multiplexed immunohistochemistry confirmed that SIRT1 protein was expressed more in CD8high than in CD8low compartments. Further analysis of bulk and single-cell RNA sequencing data from melanoma tissue samples suggested the expression of SIRT1 by different lymphocyte subpopulations (CD8+ T cells, CD4+ T cells and B cells). Furthermore, we showed in vivo that pharmacological SIRT1 activation increased the immunological effect of -PD-1 ICI against melanoma cells in mice, which was accompanied by an increase in T-cell infiltration and T-cell-related cytokines, including interferon (IFN)- , CCL4, CXCL9, CXCL10 and tumour necrosis factor- . In silico analysis of large transcriptional data cohorts showed that SIRT1 was positively associated with the proinflammatory T-cell chemokines CXCL9, CXCL10 and IFN- , and prolonged overall survival of patients with melanoma.

Our study deciphers the proteomics landscape in human melanoma, providing important information on the tumour microenvironment and identifying SIRT1 as having important prognostic and therapeutic implications. The area around a tumour has a big impact on how patients with a type of skin cancer called melanoma respond to treatment called immune checkpoint inhibition (or ICI for short). We still do not fully understand all the proteins in the immune system. In this study, we wanted to understand the biological processes that affect patients responses to ICI. Using different laboratory techniques and analysing data, we studied the proteins in melanoma. We found more than 145 proteins in certain tumour areas, including a protein called SIRT1 . SIRT1 slows down a particular signalling pathway in cells. Further analysis suggested that SIRT1 was expressed by different types of immune cells. In mice, we found that activating SIRT1 increased the anti-tumour effect of ICI. Data analysis showed that SIRT1 is positively associated with the increased survival of patients with melanoma. Our study explores the proteins involved in human melanoma. It provides important information on the tumour microenvironment. It also shows that the protein SIRT1 could be important for predicting outcomes and guiding treatment.