Microenvironmental regulation of the progression of oral potentially malignant disorders towards malignancy

Abstract

Oral potentially malignant disorders (OPMD) develop in a complex tissue microenvironment where they grow sustainably, acquiring oral squamous cell carcinoma (OSCC) characteristics. The malignant tumor depends on interactions with the surrounding microenvironment to achieve loco-regional invasion and distant metastases. Unlike abnormal cells, the multiple cell types in the tissue microenvironment are relatively stable at the genomic level and, thus, become therapeutic targets with lower risk of resistance, decreasing the risk of OPMD acquiring cancer characteristics and carcinoma recurrence. However, deciding how to disrupt the OPMD and OSCC microenvironments is itself a daunting challenge, since their microenvironments present opposite capacities, resulting in diverse consequences. Furthermore, recent studies revealed that tumor-associated immune cells also participate in the process of differentiation from OPMD to OSCC, suggesting that reeducating stromal cells may be a new strategy to prevent OPMD from acquiring OSCC characteristics and to treat OSCC. In this review, we discuss the characteristics of the microenvironment of OPMD and OSCC as well as new therapeutic strategies.

Keywords: immunity; microenvironment; oral potentially malignant disorder; premalignant condition; therapeutics.

Figure 1. During the development process from normal epithelia to OSCC through OPMD, immune cell populations are different in number and types

Figure 2. Multiple stromal cell types converge to support the development of OSCC

After circumventing cell-intrinsic mechanisms of apoptosis, cancer cells are subjected to elimination pressure by the immune system. Tumor cell-specific antigens play a role during this process; they are recognized by cytotoxic immune cells, leading to their destruction. Fibroblasts, macrophages, NK cells, and Th1 cells within the microenvironment also contribute to the growth-suppressive state. Chemokines (for example, CXCL9 and CXCL10) can be induced by IFNs (IFN-gamma) and TNF or CD40 ligand, and recruit Th1 cells. After recruiting Th1 cells, IFNs (IFN-gamma) could further switch the macrophage phenotype in the oral premalignant lesions to M1 macrophages. However, fibroblasts, macrophages, and Th1 cells may later become educated by the cancer to acquire pro-tumorigenic functions. NK cells may later decrease in the microenvironment of OSCC. For instance, M2 macrophages support diverse phenotypes during the process from OPMD to OSCC, including acquisition of the malignant phenotype and angiogenesis, by stimulating IFN and secreting growth factors (for example, VEGF). As OPMD acquire a malignant phenotype, immunosuppressor cells (For example, MDSCs) are mobilized into the circulation to disrupt immune surveillance through multiple mechanisms, including, but not limited to, disruption of antigen presentation by DCs, inhibition of T_c cells, altering M1 macrophage polarization, and inhibition of NK cell cytotoxicity. CAFs, which become generated by cell factor (For example, TGF-β1, 15-HETE, and FSP1) activated by growth factors and cytokines (For example, TGF-β, MCP1, PDGF, and FGF), and secrete factors to support carcinogenesis (For example, VEGF). MCs aggravate the progression from OPMD to OSCC by secreting mediators, including IL-1, tryptase, chymase, MMPs, histamine, and eosinophilic chemotactic factor. In addition to cellular conditions, several extracellular properties contribute to the development of malignancy, including immune evasion, hypoxia, inflammation, and angiogenic switch. EndMT, endothelial-to-mesenchymal transition; Ag, antigen; TNF, tumor necrosis factor.

Figure 3. The generation of tumor immunity is a cyclic process that can be self-propagating, leading to the accumulation of immuno-stimulatory factors that, in principle, should amplify and broaden adaptive immune responses

This cycle can be divided into six major steps, starting with the release of antigens from the cancer cells and ending with the killing of cancer cells, which can be regulated by innate immune cells (NK cells, macrophages, and Th1 cells). The process is described above, with the primary cell types involved. APCs, antigen-presenting cells.

Figure 4. Therapeutic strategies to re-educate the OPMD (using OLP for as an example) microenvironment

Multiple strategies to target the microenvironment are currently tested in clinical trials, as indicated here, and referenced throughout the review. Immune activation, marked by stimulating T cells (e.g., thalidomide and levamisole), M1 (e.g., thalidomide and curcumin), and NK cells (e.g., thalidomide), is also a promising avenue of therapeutic intervention. Sequestration of cytokines within the microenvironment, in particular T cells (e.g., steroid, mycophenolate mofetil, and Azathioprine) and B cells (e.g., steroid and mycophenolate mofetil), can be achieved by inhibiting key cytokine pathways or NF-κB signaling pathway (e.g., steroid, mycophenolate mofetil, and calcineurin inhibitors). Alternatively, “piece meal degranulation” of mast cells can be blocked by using Aloe Vera gel and calcineurin inhibitors.