Immune checkpoints are inhibitory receptor/ligand pairs regulating immunity that are exploited as key targets of anti-cancer therapy. Although the PD-1/PD-L1 pair is one of the most studied immune checkpoints, several aspects of its biology remain to be clarified. It has been established that PD-1 is an inhibitory receptor up-regulated by activated T, B, and NK lymphocytes and that its ligand PD-L1 mediates a negative feedback of lymphocyte activation, contributing to the restoration of the steady state condition after acute immune responses. This loop might become detrimental in the presence of either a chronic infection or a growing tumor. PD-L1 expression in tumors is currently used as a biomarker to orient therapeutic decisions; nevertheless, our knowledge about the regulation of PD-L1 expression is limited. The present review discusses how NF-κB, a master transcription factor of inflammation and immunity, is emerging as a key positive regulator of PD-L1 expression in cancer. NF-κB directly induces PD-L1 gene transcription by binding to its promoter, and it can also regulate PD-L1 post-transcriptionally through indirect pathways. These processes, which under conditions of cellular stress and acute inflammation drive tissue homeostasis and promote tissue healing, are largely dysregulated in tumors. Up-regulation of PD-L1 in cancer cells is controlled via NF-κB downstream of several signals, including oncogene- and stress-induced pathways, inflammatory cytokines, and chemotherapeutic drugs. Notably, a shared signaling pathway in epithelial cancers induces both PD-L1 expression and epithelial–mesenchymal transition, suggesting that PD-L1 is part of the tissue remodeling program. Furthermore, PD-L1 expression by tumor infiltrating myeloid cells can contribute to the immune suppressive features of the tumor environment. A better understanding of the interplay between NF-κB signaling and PD-L1 expression is highly relevant to cancer biology and therapy.

Cellular senescence represents a robust tumor-protecting mechanism that halts the proliferation of stressed or premalignant cells. However, this state of stable proliferative arrest is accompanied by the Senescence-Associated Secretory Phenotype (SASP), which entails the copious secretion of proinflammatory signals in the tissue microenvironment and contributes to age-related conditions, including, paradoxically, cancer. Novel therapeutic strategies aim at eliminating senescent cells with the use of senolytics or abolishing the SASP without killing the senescent cell with the use of the so-called “senomorphics”. In addition, recent works demonstrate the possibility of modifying the composition of the secretome by genetic or pharmacological intervention. The purpose is not to renounce the potent immunostimulatory nature of SASP, but rather learning to modulate it for combating cancer and other age-related diseases. This review describes the main molecular mechanisms regulating the SASP and reports the evidence of the feasibility of abrogating or modulating the SASP, discussing the possible implications of both strategies.

The discovery that the mammalian genome is largely transcribed and that almost half of the polyadenylated RNAs is composed of noncoding RNAs has attracted the attention of the scientific community. Growing amount of data suggests that long noncoding RNAs (lncRNAs) are a new class of regulators involved not only in physiological processes, such as imprinting and differentiation, but also in cancer progression and neurodegeneration. Apoptosis is a well regulated type of programmed cell death necessary for correct organ development and tissue homeostasis. Indeed, cancer cells often show an inhibition of the apoptotic pathways and it is now emerging that overexpression or downregulation of different lncRNAs in specific types of tumors sensitize cancer cells to apoptotic stimuli. In this review we summarize the latest studies on lncRNAs and apoptosis with major attention to those performed in cancer cells and in healthy cells upon differentiation. We discuss the new perspectives of using lncRNAs as targets of anticancer drugs. Finally, considering that lncRNA levels have been reported to have a correlation with specific cancer types, we argue the possibility of using lncRNAs as tumor biomarkers.

Glioma is a CNS tumor with few therapeutic options. Recently, host microbiota has been involved in the immune modulation of different tumors, but no data are available on the possible effects of the gut–immune axis on brain tumors. Here, we investigated the effect of gut microbiota alteration in a syngeneic (GL261) mouse model of glioma, treating mice with two antibiotics (ABX) and evaluating the effects on tumor growth, microbe composition, natural killer (NK) cells and microglia phenotype. We report that ABX treatment (i) altered the intestinal microbiota at family level, (ii) reduced cytotoxic NK cell subsets, and (iii) altered the expression of inflammatory and homeostatic proteins in microglia. All these findings could contribute to the increased growth of intracranial glioma that was observed after ABX treatment. These results demonstrate that chronic ABX administration alters microbiota composition and contributes to modulate brain immune state paving the way to glioma growth.

Microglia are patrolling cells that sense changes in the brain microenvironment and respond acquiring distinct phenotypes that can be either beneficial or detrimental for brain homeostasis. Anti-inflammatory microglia release soluble factors that might promote brain repair; however, in glioma, anti-inflammatory microglia dampen immune response and promote a brain microenvironment that foster tumor growth and invasion. The chemokine CXCL16 is expressed in the brain, where it is neuroprotective against brain ischemia, and it has been found to be over-expressed in glioblastoma (GBM). Considering that CXCL16 specific receptor CXCR6 is diffusely expressed in the brain including in microglia cells, we wanted to investigate the role of CXCL16 in the modulation of microglia cell activity and phenotype, and in the progression of glioma. Here we report that CXCL16 drives microglia polarization toward an anti-inflammatory phenotype, also restraining microglia polarization toward an inflammatory phenotype upon LPS and IFNγ stimulation. In the context of glioma, we demonstrate that CXCL16 released by tumor cells is determinant in promoting glioma associated microglia/macrophages (GAMs) modulation toward an anti-inflammatory/pro-tumor phenotype, and that cxcr6ko mice, orthotopically implanted into the brain with GL261 glioma cells,survive longer compared to wild-type mice. We also describe that CXCL16/CXCR6 signaling acts directly on mouse glioma cells, as well as human primary GBM cells, promoting tumor cell growth, migration and invasion. All together these data suggest that CXCL16 signaling could represent a good target to modulate microglia phenotype in order to restrain inflammation or to limit glioma progression.