Cellular and gene signatures of tumor-infiltrating dendritic cells and natural-killer cells predict prognosis of neuroblastoma

Abstract

Tumor-infiltrating lymphocytes play an essential role in improving clinical outcome of neuroblastoma (NB) patients, but their relationship with other tumor-infiltrating immune cells in the T cell-inflamed tumors remains poorly investigated. Here we show that dendritic cells (DCs) and natural killer (NK) cells are positively correlated with T-cell infiltration in human NB, both at transcriptional and protein levels, and associate with a favorable prognosis. Multiplex imaging displays DC/NK/T cell conjugates in the tumor microenvironment of low-risk NB. Remarkably, this connection is further strengthened by the identification of gene signatures related to DCs and NK cells able to predict survival of NB patients and strongly correlate with the expression of PD-1 and PD-L1. In summary, our findings unveil a key prognostic role of DCs and NK cells and indicate their related gene signatures as promising tools for the identification of clinical biomarkers to better define risk stratification and survival of NB patients.

The Natural Killer–Dendritic Cell Immune Axis in Anti-Cancer Immunity and Immunotherapy

“…This pathway is abrogated by the presence of tumor-derived prostaglandin E2 (PGE 2 ), which leads to impaired NK cell function and downregulation of CCR5 and XCR1 receptors on cDC1s ( 16 ). CCL5 expression has further been linked to NK cells and the abundance of cDC1s in neuroblastoma patient samples ( 26 ). NK cells also produce FLT3LG, the formative cytokine for cDC1s, in the TME ( 17 ) ( Figure 1 ).…”

“…in ( 2 , 7 , 11 , 12 )], and have a role in cancer prevention ( 13 ). NK cell abundance in the tumor microenvironment (TME) is associated with greater overall survival in patients with melanoma ( 14 – 18 ), hepatocellular carcinoma ( 19 ), pulmonary adenocarcinoma ( 20 ), renal cell carcinoma ( 21 ), gastric cancer ( 22 ), breast cancer ( 23 ), squamous cell lung cancer ( 24 ), non-small cell lung cancer ( 25 ), and neuroblastoma ( 26 ). The protective immunity provided by NK cells is controlled by their direct cytotoxicity and the production of immunomodulatory cytokines and chemokines that sculpt local and distant immune cell responses [rev.…”

Data analytics and clinical feature ranking of medical records of patients with sepsis

“…In this context, machine learning and artificial intelligence applied to electronic health records (EHRs) of patients diagnosed with sepsis can provide cheap, fast, non-invasive and effective methods that are able to predict the aforementioned targets (septic shock, survival, and SOFA score), and to detect the most predictive symptoms and risk factors from the features available in the electronic health records. Scientists, in fact, already took advantage of machine learning for survival or diagnosis prediction and for clinical feature ranking several times in the past [2], for example to analyze datasets of patients having heart failure [3,4], mesothelioma [5], neuroblastoma [6][7][8], and breast cancer [9].…”

Dendritic Cells: Behind the Scenes of T-Cell Infiltration into the Tumor Microenvironment

“…Interestingly, the identified DC gene signature includes transcripts typically expressed by NK cells, and conversely, the NK gene signature includes the BTLA transcript that is typically expressed by DCs, thus confirming the existence of a DC-NK cell axis also in neuroblastoma. This hypothesis was further strengthened by multiplexed immunofluorescence imaging which clearly shows the interaction between DCs and NK cells, both with each other and with CD8 + T cells, within the tumor nests of low-risk neuroblastoma patients [ 85 ]. Moreover, the FLT3L and CCL5 genes both strongly correlated with DC, NK cell and T cell abundance, thus further validating the existence of a DC-NK cell axis that promotes CD8 + T cell antitumor immunity in this pediatric malignancy.…”

“…The high density of TLS-associated DCs correlates with long-term survival and high expression of genes related to T-cell activation, Th1 phenotype, and cytotoxic activity [ 92 ]. In human neuroblastoma, DCs were sparsely distributed or localized within the TLS, and significantly correlated with the abundance of tumor-infiltrating T cells and NK cells, both at the transcriptional and protein levels, and associated with favorable prognosis [ 85 ]. Interestingly, high expression of DC and NK cell-gene signatures were predictors of good prognosis not only in patients with neuroblastoma, but also in patients with colorectal cancer, skin cutaneous melanoma, head and neck squamous cell carcinoma and breast cancer [ 85 ], thus representing a robust prognostic tool to be added to those currently used, in addition to the T-cell infiltration score [ 93 , 94 ].…”