Oral Mucositis: An Update on Innate Immunity and New Interventional Targets

Abstract

Oral mucositis (OM), a common debilitating toxicity associated with chemo- and radiation therapies, is a significant unmet clinical need for head and neck cancer patients. The biological complexities of chemoradiotherapy-induced OM involve interactions among disrupted tissue structures, inflammatory infiltrations, and oral microbiome, whereby several master inflammatory pathways constitute the complicated regulatory networks. Oral mucosal damages triggered by chemoradiotherapy-induced cell apoptosis were further exacerbated by the amplified inflammatory cascades dominantly governed by the innate immune responses. The coexistence of microbiome and innate immune components in oral mucosal barriers indicates that a signaling hub coordinates the interaction between environmental cues and host cells during tissue and immune homeostasis. Dysbiotic shifts in oral microbiota caused by cytotoxic cancer therapies may also contribute to the progression and severity of chemoradiotherapy-induced OM. In this review, we have updated the mechanisms involving innate immunity-governed inflammatory cascades in the pathobiology of chemoradiotherapy-induced OM and the development of new interventional targets for the management of this severe morbidity in head and neck cancer patients.

Keywords: chemotherapy; immunotherapy; inflammatory; microbiota; radiation; tissue homeostasis.

Figure 1.

New pathways regulating inflammation and wound healing in mucositis. (A) Smad7 activation inhibits transforming growth factor–β (TGF-β) signaling for promoting epithelial tissue regeneration and nuclear factor κB (NF-κB) signaling for inflammation resolution. (B) Reactive oxygen species (ROS) induces mammalian target of rapamycin (mTOR) signaling activation in mucositis. Rapamycin, as a specific mTOR inhibitor, promotes wound healing and epithelial cell rejuvenation in mucositis. (C) Chemo- and radiotherapy-induced DNA damage response and cell cycle activation cause apoptosis in Lgr5⁺ epithelial stem cells. Cell cycle inhibitors or Wnt activator R-Spondin1 (RSpo1) can increase epithelial stem cell survival and tissue regeneration in mucositis. DDR, DNA damage response; PUMA, P53-upregulated modulator of apoptosis; ROS, reactive oxygen species.

Figure 2.

Signaling hub coordinates innate immunity and microbiome in mucositis. (A) Epithelial cells as the primary barrier between the outside environment and the host extensively express innate immune receptors for microbial recognition to maintain tissue/organ homeostasis. (B) Macrophage dynamic polarization plays a key role in the coordination of immune response, inflammation, and tissue remodeling/homeostasis during mucositis progression. (C) Innate lymphoid cells (ILCs) respond to intracellular and extracellular pathogens and contribute to tissue maintenance and repair. DAMPs, damage-associated molecular patterns; DCs, dendritic cells; HMGB1, high-mobility group box 1; IL, interleukin; NLRPs, nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing; PAMPs, pathogen-associated molecular patterns; TGFβ, transforming growth factor β; TLR, Toll-like receptor; VEGF, vascular endothelial growth factor.

Figure 3.

Potential mode of action of mesenchymal stromal cell (MSC)–based regenerative therapy. Exogenous MSCs home to the injury site following in vivo transplantation, where a small proportion of engrafted MSCs transdifferentiate into certain types of cells to replace those damaged ones while some of them interact with various types of host cells and exert multiple biological functions (e.g., proproliferation, proangiogenesis, anti-inflammation, antiapoptosis, and antioxidant) via their secretion of a myriad of trophic factors, thus contributing to the establishment of proregenerative microenvironment that is favorable to tissue regeneration (Akiyama et al. 2012; Zhang et al. 2012; Chang et al. 2017; Elsaadany et al. 2017; Van de Putte et al. 2017).