Epigenetic and Transcriptional Regulation of Innate Immunity in Cancer

Abstract

Innate immune cells participate in the detection of tumor cells via complex signaling pathways mediated by pattern-recognition receptors, such as Toll-like receptors and nucleotide-binding and oligomerization domain-like receptors. These pathways are finely tuned via multiple mechanisms, including epigenetic regulation. It is well established that hematopoietic progenitors generate innate immune cells that can regulate cancer cell behavior, and the disruption of normal hematopoiesis in pathologic states may lead to altered immunity and the development of cancer. In this review, we discuss the epigenetic and transcriptional mechanisms that underlie the initiation and amplification of innate immune signaling in cancer. We also discuss new targeting possibilities for cancer control that exploit innate immune cells and signaling molecules, potentially heralding the next generation of immunotherapy.

Figure 1.

Innate immune signaling pathways. TNF binding to TNFR1 triggers the assembly of LUBAC complex, and the activation of TAK1 and subsequently IKK. TLR4, or IL1R1 triggers the interaction of the MyD88-IRAK complex, which engages TRAF6. Activated TLR4 can also be endocytosed and signaled via RIPK1. RIG1 binding to dsRNA promotes its association to MAVS complex, which converges on TRAF6. MAVS also interacts with TRAF3, TBK1, and STING to activate IRF3 and IRF7. NLRP3 triggers secretion of IL1b and IL18.

Figure 2.

Trained immunity. Challenge of innate immune cells and HSPCs with training stimuli induces changes in cell signaling and metabolism. Specific TFs, such as NF-κB or AP-1, and epigenetic enzymes, induce chromatin and DNA modifications, and regulate gene transcription. Expression of these genes in turn feeds the machinery of innate immunity and promotes cytokine secretion.