Recent years have seen a renaissance in the research linking inflammation and cancer with immune cells playing a central role in smouldering inflammation in the tumor microenvironment

Recent years have seen a renaissance in the research linking inflammation and cancer with immune cells playing a central role in smouldering inflammation in the tumor microenvironment. then explain the recently-explored strategies of immunomodulation and discuss some important methods via an immunology perspective. [17]. Indeed, we as well as others have shown that tumor-conditioned tumor-associated macrophages (TAMs) exhibit a mixed M1/M2 macrophage phenotype, expressing both XL184 free base (Cabozantinib) M2 (CD163 and CD206) and M1 (IL-1, IL-6, TNF-, and CCL3) markers [18,19]. TAMs promote malignancy metastasis through a number of mechanisms including promoting angiogenesis, inducing tumor growth and enhancing tumor-cell migration and invasion [20]. Thus unsurprisingly, clinical data have shown a correlation between the quantity of TAMs in the tumor microenvironment (TME) XL184 free base (Cabozantinib) and poor prognosis for breast, prostate, ovarian, cervical, endometrial, esophageal and bladder cancers [20]. TAMs express vascular endothelial growth factor-C (VEGF-C), VEGF-D and VEGFR-3, all of which are essential for lymphatic vessel formation, angiogenesis and metastasis [21]. Indeed, TAM depletion using clodronate liposomes and angiogenesis inhibition using anti-VEGF antibodies significantly reduces tumorigenesis [22]. TAM depletion in the TME may, therefore, be a potential anti-tumoral strategy to inhibit tumor progression. TAMs also promote tumorigenesis through immunosuppression and XL184 free base (Cabozantinib) inhibiting anti-tumoral immunity as shown both and in mouse studies. TAMs can enhance tumor evasion of the immune surveillance system in two ways: (1) by directly inhibiting anti-tumoral cytotoxic CD8+ T cell responses via PD-L1/PD-L2 expression [23]; and (2) by secreting immunosuppressive cytokines and proteases such as arginase-1, IL-10, TGF- and prostaglandins, which prevent T cell activation [17,24,25]. 2.2. Neutrophils Many and studies have highlighted that neutrophils, like macrophages, also have crucial functions in mediating tumor progression [26]. Polymorphonuclear neutrophils are the most abundant circulating leukocyte in humans. They are innate immune cells involved in the first line of defence against infections, and thus have an indispensable role in the inflammatory response. During an infection, activated neutrophils release proteinases into the microenvironment that damage surrounding tissues. They also produce cytokines and chemokines that recruit other inflammatory cells and alter the immune response [27]. However in cancer settings, these cells are not mere bystanders; neutrophil recruitment and activation has been observed in tumors and displays a state of host inflammation [2]. Neutrophils are involved in various stages of tumorigenesis including tumor initiation, proliferation and metastasis [28,29]. They infiltrate tumors in large numbers and both studies as well as patient studies that were performed in the 1980s showed that neutrophils can kill tumor cells and mediate tumor cytotoxicity [30,31]. The pro-tumoral functions of neutrophils, however, have only been shown relatively recently. As such, the current literature explains tumor-associated neutrophils (TANs) as a double-edged sword, performing both anti-tumoral and pro-tumoral functions [26,[32], [33], [34]]. Tumor growth initiation can be induced by ROS, reactive nitrogen species or protease release by TANs [35]. ROS production by neutrophils is an effective mechanism to kill microorganisms and is important in the early stages of tumor development, where ROS-induced apoptotic signaling kills tumor cells [36]. However, in cases where neutrophil-derived ROS is not sufficient to kill tumor cells, Serpinf2 it can indirectly promote tumor growth through DNA damage and genotoxicity [37]. The impaired immune response reported in malignancy patients correlates with exposure to oxidative stress. As such, the elevated ROS levels produced by activated neutrophils are considered an obstacle for effective malignancy immunotherapy [38]. In advanced malignancy patients, activated TANs and their production of hydrogen peroxide is the underlying cause of impaired T cell function and suppression [39]. Hydrogen peroxide suppresses cytokine production by normal T cells and reduces T cell receptor zeta chain expression, leading to immunosuppression [39]. For example, the exposure of memory and effector CD45RO+ T cells to ROS blocks their NF-B activation and reduces Th1 cytokine production [38]. XL184 free base (Cabozantinib) Furthermore, murine studies have exhibited that ROS can lead to CD8+ T cell tolerance by nitration of tyrosines within the TCR/CD8 complex and subsequently preventing specific peptideCMHC dimers from binding to CD8+ T cells [40]. Consequently, CD8+.