Cancer
Immunological memory has also been established to play a central role in tumor progression. For example, β-glucan-induced mouse granulocyte immune memory is reportedly associated with diminished tumor growth, with this anti-tumor effect being attributed to a reprogramming of neutrophils toward an anti-tumor phenotype, a process dependent on type I interferon signaling, although independent of host adaptive immunity67. Indeed, innate immune cells may play opposing roles by displaying both tumor-suppressing and tumor-promoting properties. For example, in terms of suppression, BCG treatment has long been known to eradicate malignancies such as bladder cancer and melanoma and reduce the risk of leukemia and lymphoma 68-71. Furthermore, β-glucan has also been used in clinical trials for cancer therapy such as that for non-small cell lung, breast, and colorectal cancers 72. The findings of further studies have revealed that such anti-tumor effects may be attributable to the non-specific protection triggered by epigenetic reprogramming and is associated with the induction of monocyte/macrophage memory31, 73.
With respect to the tumor-promoting effects of macrophage memory, tumor-associated macrophage (TAM), which serves as important immune regulatory element in tumor progression, has been shown to be involved in the development of an immunosuppressive tumor microenvironment and facilitate tumor immune escape, growth, and metastasis74, 75. The salient feature of TAM differentiation is epigenetic reprogramming involving histone modification, such as H3K4me3 and H3K9me3 alterations in the promoter regions of IL-6 and TNF-α, thereby inducing the production of pro-inflammatory cytokines and expression of tumor-associated gene profiles 76. For example, predominant functional changes in thyroid cancer (TC)-induced macrophage memory enhance inflammatory properties and the modification of cell metabolism. This functional reprogramming has been established to be partially mediated by TC-derived lactate via AKT1/mTOR-dependent aerobic glycolysis, resulting in long-term epigenetic modifications at histone methylation levels, such as H3K4me3 and H3K9me3 in the promoters of IL-6 and TNF-α, thereby leading to increases in the expression of genes characteristic of cancer tumor profiles, and an increase in the production of TAM pro-inflammatory factors 76, 77.