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Cancer stem cells (CSCs) have drawn much attention as important tumour-initiating cells that may also be crucial for recurrence after chemotherapy. Although the activity of CSCs in various forms of cancer is complex and yet to be fully elucidated, opportunities for therapies targeting CSCs exist. CSCs are molecularly distinct from bulk tumour cells, so they can be targeted by exploiting their signature molecular pathways. Inhibiting stemness has the potential to reduce the risk posed by CSCs by limiting or eliminating their capacity for tumorigenesis, proliferation, metastasis, and recurrence. Here, we briefly described the role of CSCs in tumour biology, the mechanisms involved in CSC therapy resistance, and the role of the gut microbiota in cancer development and treatment, to then review and discuss the current advances in the discovery of microbiota-derived natural compounds targeting CSCs. Collectively, our overview suggests that dietary intervention, toward the production of those identified microbial metabolites capable of suppressing CSC properties, is a promising approach to support standard chemotherapy.

Myeloid-derived suppressor cells (MDSCs) contribute to the induction of an immune suppressive/anergic, tumor permissive environment. MDSCs act as immunosuppression orchestrators also by interacting with several components of both innate and adaptive immunity. Natural killer (NK) cells are innate lymphoid cells functioning as primary effector of immunity, against tumors and virus-infected cells. Apart from the previously described anergy and hypo-functionality of NK cells in different tumors, NK cells in cancer patients show pro-angiogenic phenotype and functions, similar to decidual NK cells. We termed the pro-angiogenic NK cells in the tumor microenvironment "tumor infiltrating NK" (TINKs), and peripheral blood NK cells in cancer patients "tumor associated NK" (TANKs). The contribution of MDSCs in regulating NK cell functions in tumor-bearing host, still represent a poorly explored topic, and even less is known on NK cell regulation of MDSCs. Here, we review whether the crosstalk between MDSCs and NK cells can impact on tumor onset, angiogenesis and progression, focusing on key cellular and molecular interactions. We also propose that the similarity of the properties of tumor associated/tumor infiltrating NK and MDSC with those of decidual NK and decidual MDSCs during pregnancy could hint to a possible onco-fetal origin of these pro-angiogenic leukocytes.

The link between cancer development or progression and immune system dysregulation has long been established. Virtually every cell type belonging to both the innate and adaptive immune system has been reported to be involved in a complex interplay that might culminate into either a pro- or anti-tumorigenic response. Among the cellular components of the innate immune system, cells belonging to the monocyte/macrophage lineage have been consistently shown to play a key role in the tumorigenic process. The most advanced human tumors are reported to be strongly infiltrated with Tumor-Associated Macrophages (TAMs) endowed with the ability to contribute to tumor growth and dissemination. However, given their widely acknowledged functional plasticity, macrophages can display anti-tumor properties as well. Based on these premises, experimental approaches to promote the in vivo macrophage shift from pro-tumor to anti-tumor phenotype represent one of the most promising research field aimed at developing immune system-mediated tumor suppressive therapies. In this context, the human RNASET2 oncosuppressor gene has emerged as a potential tool for macrophage-mediated tumor suppression. A growing body of experimental evidence has been reported to suggest a role for this gene in the regulation of macrophage activity in both in vitro and in vivo experimental models. Moreover, several recent reports suggest a role for this gene in a broad range of cell types involved in immune response, pointing at RNASET2 as a putative regulator of several functional features within the immune system.

NK cells are effector lymphocytes involved in tumor immunosurveillance; however, in patients with solidmalignancies,NKcells have compromised functions.Wehave previously reported that lung tumor-associated NKcells (TANKs; peripheralblood) andtumor-infiltratingNKcells (TINK s ) showproangiogenic,decidualNK-like (dNK) phenotype. In this study, we functionally andmolecularly investigated TINK s and TANK s fromblood and tissue samples of patients with colorectal cancer (CRC), a neoplasmin which inflammation and angiogenesis have clinical relevance, and compared them to NK cells from controls and patients with nononcologic inflammatory bowel disease. CRC TINK s /TANK s showed decreased expression for the activatory marker NKG2D, impaired degranulation activity, a decidual-likeNKpolarization toward the CD5 6bright CD16 dim/- 2CD9 + CD49 + subset. TINKs and TANKs secreted cytokines with proangiogenic activities, and induce endothelial cell proliferation, migration, adhesion, and the formation of capillary-like structures in vitro. dNK cells release specific proangiogenic factors; amongwhich, angiogenin and invasion-associated enzymes related to theMMP9-TIMP1/2 axis.Here,we describe, for the first time, to our knowledge, the expression of angiogenin,MMP2/9, and TIMP by TANK s in patients with CRC. This phenotype could be relevant to the invasive capabilities and proangiogenic functions of CRC-NK cells and become a novel biomarker. STAT3/STAT5 activation was observed in CRC-TANK s , and treatment with pimozide, a STAT5 inhibitor, reduced endothelial cell capability to form capillary-like networks, inhibiting VEGF and angiogenin production without affecting the levels of TIMP1, TIMP2, and MMP9, indicating that STAT5 is involved in cytokine modulation but not invasion-associated molecules. Combination of Stat5 orMMP inhibitors with immunotherapy could help repolarizeCRCTINK s and TANK s to anti-tumor antimetastatic ones.

Non-small cell lung cancer (NSCLC), the most frequent lung cancer (80%), can be phenotypically classified into two main subtypes: squamous cell carcinoma (SCC) and adenocarcinoma (ADC). While SCC has relatively rapid doubling times from the onset, ADC has longer doubling times initially that become reduced during tumor progression, suggesting a key role for the microenvironment. During lung tumor progression, a complex and dynamic interplay occurs between proliferating tumor cells and stromal, endothelial and immune tumor-conditioned host cells within the tumor microenvironment (TUMIC). Several factors within the TUMIC, such as hypoxia, cytokines and soluble factors, appear to blunt the anti-tumor immune response and polarize immune cells towards a pro-tumor phenotype. Phenotypically and functionally altered immune cells found in cancer patients include macrophages, neutrophils, myeloid, dendritic, and even NK cells. We studied tumor infiltrating (TINK) and tumor associated (TANK) NK cells in NSCLC. NSCLC TINKs and TANKs show similarities to decidual NK cells, being polarized toward tissue builders, rather than killers, and producing pro-angiogenic cytokines. The functionally polarized immune cells in NSCLC provide the stromal support and neovascularization required for NSCLC tumor expansion and progression in a feed-forward mechanism, leading to tumor progression. Further, systemic alterations of immune cells are also present in NSCLC patients. The precise knowledge of these immune cell alterations within the TUMIC has become crucial for diagnosis, targeted therapeutic intervention, as well as prevention, of NSCLC cancer