Trained Immunity for Personalized Cancer Immunotherapy: Current Knowledge and Future Opportunities

Abstract

Memory formation, guided by microbial ligands, has been reported for innate immune cells. Epigenetic imprinting plays an important role herein, involving histone modification after pathogen-/danger-associated molecular patterns (PAMPs/DAMPs) recognition by pattern recognition receptors (PRRs). Such "trained immunity" affects not only the nominal target pathogen, yet also non-related targets that may be encountered later in life. The concept of trained innate immunity warrants further exploration in cancer and how these insights can be implemented in immunotherapeutic approaches. In this review, we discuss our current understanding of innate immune memory and we reference new findings in this field, highlighting the observations of trained immunity in monocytic and natural killer cells. We also provide a brief overview of trained immunity in non-immune cells, such as stromal cells and fibroblasts. Finally, we present possible strategies based on trained innate immunity that may help to devise host-directed immunotherapies focusing on cancer, with possible extension to infectious diseases.

Keywords: cancer; dendritic cells; immune responses; immunotherapy; inflammation; macrophages; pathogens; trained immunity.

FIGURE 1

Possible immunological processes potentiated by trained innate immunity against infections and cancer. The schematic represents some of the cardinal immune mechanisms at play in establishing trained immunity in monocytic cells, including macrophages and DCs. Bacteria-/fungi-exposed monocytes or macrophages (in response to bacterial LPS or fungal zymosan detected by pathogen recognition receptors TLR4 and Dectin-1, for example) can cross-react to either pathogen type with the production of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β, IL-18, IL-12, and IL-23) which are necessary for T-cell activation. Myd88 and/or TRIF/TRAM-mediated IRF5 activity appears to play an important role herein, along with epigenetic modification (largely involving methylation patterns) of histone 3 at position lysine 4 (H3K4). Antigen presentation via the HLA class I and class II (HLA-DR is shown in the schematic) and the inflammatory tissue environment would promote priming and expansion of T helper, cytotoxic T lymphocyte (CTL) and TCR γδ T-cell populations. These T cells can eliminate infected cells and control the spread of the pathogen, and possibly react to dysplastic cells which may develop due to inflammation-driven genetic aberrations. Similarly, there may also be a direct effect of the innate immune cells – trained by exposure to pathogens – to produce an inflammation-driven response to future infections as well as cancer cells. The latter may express both classes of HLA molecules, only the TCR γδ ligands MICA/B (which also binds to NKG2D on NK cells as well as γδ T cells), a combination of the two or HLA class II alone in the event of mutational events leading to HLA class I loss. Ongoing inflammation in tissue leads to the production of several cytokines and growth factors (e.g., TGF-β, EGF, IL-6, IL-10, and VEGF) by infected cells, dysplastic tissue and cells in the stromal compartment (activated stem cells, fibroblasts), potentially exerting a pro-tumor effect and impairing the host’s anti-tumor response. The cytokine microenvironment and the possible infection with virus, such as CMV, may also promote the development of memory NK cells in tissue. Mo, monocyte; Mf, macrophage; DC, dendritic cell; HLA, human leukocyte antigen; LPS, lipopolysaccharide; IRF5, interferon regulatory factor 5; IFN-γ, interferon gamma; TNF-α, tumor necrosis factor alpha; GrzB, granzyme B; perf, perforin; TLR, Toll-like receptor; TRIF, TIR-domain-containing adapter-inducing interferon-β; TRAM, TRIF-related adaptor molecule; Me, methyl group; TGF-β, transforming growth factor beta; EGF, epidermal growth factor; VEGF, vascular endothelial growth factor; NK, natural killer cell.