The pathophysiological roles of mast cells are still not fully understood, over 140 years since their description by Paul Ehrlich in 1878. Initial studies have attempted to identify distinct “subpopulations” of mast cells based on a relatively small number of biochemical characteristics. More recently, “subtypes” of mast cells have been described based on the analysis of transcriptomes of anatomically distinct mouse mast cell populations. Although mast cells can potently alter homeostasis, in certain circumstances, these cells can also contribute to the restoration of homeostasis. Both solid and hematologic tumors are associated with the accumulation of peritumoral and/or intratumoral mast cells, suggesting that these cells can help to promote and/or limit tumorigenesis. We suggest that at least two major subsets of mast cells, MC1 (meaning anti-tumorigenic) and MC2 (meaning pro-tumorigenic), and/or different mast cell mediators derived from otherwise similar cells, could play distinct or even opposite roles in tumorigenesis. Mast cells are also strategically located in the human myocardium, in atherosclerotic plaques, in close proximity to nerves and in the aortic valve. Recent studies have revealed evidence that cardiac mast cells can participate both in physiological and pathological processes in the heart. It seems likely that different subsets of mast cells, like those of cardiac macrophages, can exert distinct, even opposite, effects in different pathophysiological processes in the heart. In this chapter, we have commented on possible future needs of the ongoing efforts to identify the diverse functions of mast cells in health and disease.

Human neutrophils, the most abundant circulating leukocytes, are fundamental components of the host response against different pathogens. Until a few years ago, neutrophils received limited attention in cancer immunology. Recently, it was discovered that both circulating, and tumor-associated, neutrophils possess functional plasticity when exposed to various inflammatory stimuli and in the tumor microenvironment. Neutrophils and their mediators can exert several pro-tumor activities in cancer and promote metastasis through different mechanisms. Angiogenesis plays a pivotal role in inflammation and tumor growth. Activated human neutrophils release several angiogenic factors [vascular endothelial growth factor-A (VEGF-A), angiopoietin-1 (ANGPT1), CXCL8, hepatocyte growth factor (HGF), and metalloproteinase 9 (MMP-9)] and form neutrophil extracellular traps (NETs). NETs promote tumor growth and metastasis formation through several mechanisms: they can awake dormant cancer cells, capture circulating tumor cells, coat and shield cancer cells, thus preventing CD8⁺- and natural killer (NK) cell-mediated cytotoxicity. ANGPTs released by endothelial and periendothelial mural cells induce platelet-activating factor (PAF) synthesis and neutrophil adhesion to endothelial cells. NETs can directly exert several proangiogenic activities in human endothelial cells and NETs induced by ANGPTs and PAF increase several aspects of angiogenesis in vitro and in vivo. A better understanding of the pathophysiological functions of NETs in cancer and angiogenesis could be of importance in the early diagnosis, prevention and treatment of tumors.

Immune cells play critical roles in tumor prevention as well as initiation and progression. However, immune-resistant cancer cells can evade the immune system and proceed to form tumors. The normal microenvironment (immune cells, fibroblasts, blood and lymphatic vessels, and interstitial extracellular matrix (ECM)) maintains tissue homeostasis and prevents tumor initiation. Inflammatory mediators, reactive oxygen species, cytokines, and chemokines from an altered microenvironment promote tumor growth. During the last decade, thyroid cancer, the most frequent cancer of the endocrine system, has emerged as the fifth most incident cancer in the United States (USA), and its incidence is steadily growing. Inflammation has long been associated with thyroid cancer, raising critical questions about the role of immune cells in its pathogenesis. A plethora of immune cells and their mediators are present in the thyroid cancer ecosystem. Monoclonal antibodies (mAbs) targeting immune checkpoints, such as mAbs anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA-4) and anti-programmed cell death protein-1/programmed cell death ligand-1 (anti-PD-1/PD-L1), have revolutionized the treatment of many malignancies, but they induce thyroid dysfunction in up to 10% of patients, presumably by enhancing autoimmunity. Combination strategies involving immune checkpoint inhibitors (ICIs) with tyrosine kinase (TK) or serine/threonine protein kinase B-raf (BRAF) inhibitors are showing considerable promise in the treatment of advanced thyroid cancer. This review illustrates how different immune cells contribute to thyroid cancer development and the rationale for the antitumor effects of ICIs in combination with BRAF/TK inhibitors.

Helicobacter pylori-derived peptide RpL1 aa 2–20 (Hp(2–20)) in addition to its antimicrobial action exerts several immunomodulatory effects in eukaryotic cells by interacting with formyl peptide receptors (FPRs). It has recently been shown that activation of FPRs facilitates intestinal epithelial cell restitution. We investigated whether Hp(2–20) induces healing of injured gastric mucosa and assessed the mechanisms underlying any such effect. We investigated the expression of FPRs in two gastric epithelial cell lines (MKN-28 and AGS) at mRNA and protein level. To determine whether FPRs were functional we performed chemotaxis experiments and proliferation assays and studied the Hp(2–20)-activated downstream signaling pathway. The effect of Hp(2–20) on mucosal healing was evaluated in rats after indomethacin-induced injury. Here we show that: (1) FPRs were expressed in both cell lines; (2) Hp(2–20) stimulated migration and proliferation of gastric epithelial cells; (3) this effect was specifically mediated by formyl peptide receptor-like 1 (FPRL1) and FPRL2 and was associated with activation of FPR-related downstream signaling pathways; (4) Hp(2–20) up-regulated the expression and secretion of vascular endothelial growth factor; and (5) Hp(2–20) accelerated healing of rat gastric mucosa after injury brought about by indomethacin at both the macroscopic and microscopic levels. In conclusion, by interacting with FRPL1 and FPRL2, H. pylori-derived Hp(2–20) induces cell migration and proliferation, as well as the expression of vascular endothelial growth factor, thereby promoting gastric mucosal healing. This study provides further evidence of the complexity of the relationship between H. pylori and human gastric mucosa, and it suggests that a bacterial product may be used to heal gastric mucosal injury.