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Simple Summary: Therapeutic options for GEP-NETs are very limited, and at the same time, the incidence of these cancers is increasing. The evidence has shown that multiple neoplasms can be successfully treated with immune checkpoint inhibitors such as PD-1/PD-L1 inhibitors. Crucial to determining a patient's response to immunotherapy is access to the tumor microenvironment. Currently, there is no consistency regarding the future role of TME and immunotherapy in GEP-NETs. Thus, this review points to the solution in selecting a concrete patient group that, based on tumor features can benefit from immunotherapy. Neuroendocrine neoplasms (NENs) are a heterogenous and recurrent group of malignancies originating from neuroendocrine secretory cells diffused on all parts of the human body. Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) account for most NENs. Considering the abundance of possible origins, locations, and tumor specifications, there is still no consensus about optimal treatment options for these neoplasms. In light of the escalating immunotherapeutic approaches, it is crucial to define indications for such therapy in GEP-NETs. Bearing in mind the significance of pathophysiological mechanisms and tumor microenvironment (TME) impact on carcinogenesis, defining TME structure and correlation with the immune system in GEP-NETs appears essential. This paper aimed to assess the characterization of the tumor immune microenvironment for a better understanding of the possible therapeutic options in GEP-NETS. The authors performed a systematic review, extracting papers from the PubMed, Web of Science, and Scopus databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Among 3800 articles identified through database searching, 292 were assessed for eligibility. Ultimately, 28 articles were included in the qualitative synthesis. This paper sums up the research on the immune cell infiltrates, immune checkpoint expression, cytokine profile, neoangiogenesis, and microbiome in the TME of GEP-NETs. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) cells contain elevated levels of Stat3 and Smad7, two proteins involved in the growth and survival of neoplastic cells. This study was aimed at examining whether Smad7 positively controls the expression of Stat3 in CRC cells. By employing antisense technology, which specifically inhibits Smad7 expression in selected cells, we hereby show that the reduction of Smad7 in CRC cells is paralleled by the marked suppression of the levels of Stat3 and of Stat3-related genes. Finally, we provide evidence that in human CRC tissue samples, there is a positive correlation between Smad7 expression and Stat3 content. Overall, these findings delineate a novel positive feedback loop that sustains CRC cell behavior and suggest that Smad7 is a target for therapeutic intervention in patients with such a disease. Colorectal cancer (CRC) cells contain elevated levels of active signal transducer and the activator of transcription (Stat)-3, which exerts proliferative and anti-apoptotic effects. Various molecules produced in the CRC tissue can activate Stat3, but the mechanisms that amplify such an activation are yet to be determined. In this paper, we assessed whether Smad7, an inhibitor of Transforiming Growth Factor (TGF)-β1 activity, sustains Stat3 expression/activation in CRC cells. Both Smad7 and phosphorylated (p)/activated-Stat3 were more expressed in the tumoral areas of CRC patients, compared to the normal adjacent colonic mucosa of the same patients, and were co-localized in primary CRC cells and CRC cell lines. The knockdown of Smad7 with a Smad7 antisense oligonucleotide (AS) reduced p-Stat3 in both unstimulated and interleukin (IL)-6- and IL-22-stimulated DLD-1 and HCT116 cells. Consistently, reduced levels of BCL-xL and survivin, two downstream signaling targets of Stat3 activation, were seen in Smad7 AS-treated cells. An analysis of the mechanisms underlying Smad7 AS-induced Stat3 inactivation revealed that Smad7 AS reduced Stat3 RNA and protein expression. A chromatin immunoprecipitation assay showed the direct regulatory effect of Smad7 on the Stat3 promoter. RNA-sequencing data from the Tumor, Normal and Metastatic (TNM) plot database showed a positive correlation between Smad7 and Stat3 in 1450 CRC samples. To our knowledge, this is the first evidence supporting the theory that Smad7 positively regulates Stat3 function in CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Human microbiome research is rapidly expanding, including a variety of clinical medicine and public health disciplines. Commensal microbiome has a significant impact on shaping homeostasis of the organism, as well as the development of pathological states. A number of studies indicate that changes in the human microbiome could determine an oncogenic effect by, among other things, inducing chronic inflammatory response, instigating cellular antiapoptotic signals or modulation of anticancer immunity. The presence of pathogenic species also contributes to the exacerbation of the complications of the treatment applied, such as radiation-induced oral mucositis, which is the most common side effect of the treatment. A better understanding of the interplay between oral microbiome and head and neck cancers might provide an important step towards a more effective treatment for this highly malignant tumor. The following review is a complex revision of the up-to-date research on the oral microbiome and its impact on the development of head and neck cancer and radiation-induced oral mucositis. Head and neck carcinoma is one of the most common human malignancy types and it ranks as the sixth most common cancer worldwide. Nowadays, a great potential of microbiome research is observed in oncology—investigating the effect of oral microbiome in oncogenesis, occurrence of treatment side effects and response to anticancer therapies. The microbiome is a unique collection of microorganisms and their genetic material, interactions and products residing within the mucous membranes. The aim of this paper is to summarize current research on the oral microbiome and its impact on the development of head and neck cancer and radiation-induced oral mucositis. Human microbiome might determine an oncogenic effect by, among other things, inducing chronic inflammatory response, instigating cellular antiapoptotic signals, modulation of anticancer immunity or influencing xenobiotic metabolism. Influence of oral microbiome on radiation-induced oral mucositis is expressed by the production of additional inflammatory cytokines and facilitates progression and aggravation of mucositis. Exacerbated acute radiation reaction and bacterial superinfections lead to the deterioration of the patient's condition and worsening of the quality of life. Simultaneously, positive effects of probiotics on the course of radiation-induced oral mucositis have been observed. Understanding the impact on the emerging acute radiation reaction on the composition of the microflora can be helpful in developing a multifactorial model to forecast the course of radiation-induced oral mucositis. Investigating these processes will allow us to create optimized and personalized preventive measures and treatment aimed at their formation mechanism. Further studies are needed to better establish the structure of the oral microbiome as well as the dynamics of its changes before and after therapy. It will help to expand the understanding of the biological function of commensal and pathogenic oral microbiota in HNC carcinogenesis and the development of radiation-induced oral mucositis. [ABSTRACT FROM AUTHOR]

Simple Summary: The suppressors of cytokine signaling (SOCS) are known cytokine-inducible negative regulators of JAK/STAT and other cell signaling pathways. Deregulation of SOCS expression is linked to various tumor types and inflammatory diseases. While SOCS play a crucial role in the regulation of immune cell function, their roles in hematological malignancies have not been elucidated thus far. In this review, we summarize the current knowledge on the roles of SOCS in leukemia development and progression. We delineate the paradoxical activities of SOCS in different leukemia types and the regulatory mechanisms underlying SOCS deregulation in leukemia. Lastly, we discuss the possible implications of SOCS deregulation for leukemia diagnosis and prognosis. This paper provides new insights into the roles of SOCS in the pathobiology of leukemia and leukemia research. Cytokines are pleiotropic signaling molecules that execute an essential role in cell-to-cell communication through binding to cell surface receptors. Receptor binding activates intracellular signaling cascades in the target cell that bring about a wide range of cellular responses, including induction of cell proliferation, migration, differentiation, and apoptosis. The Janus kinase and transducers and activators of transcription (JAK/STAT) signaling pathways are activated upon cytokines and growth factors binding with their corresponding receptors. The SOCS family of proteins has emerged as a key regulator of cytokine signaling, and SOCS insufficiency leads to constitutive activation of JAK/STAT signaling and oncogenic transformation. Dysregulation of SOCS expression is linked to various solid tumors with invasive properties. However, the roles of SOCS in hematological malignancies, such as leukemia, are less clear. In this review, we discuss the recent advances pertaining to SOCS dysregulation in leukemia development and progression. We also highlight the roles of specific SOCS in immune cells within the tumor microenvironment and their possible involvement in anti-tumor immunity. Finally, we discuss the epigenetic, genetic, and post-transcriptional modifications of SOCS genes during tumorigenesis, with an emphasis on leukemia. [ABSTRACT FROM AUTHOR]

Simple Summary: Radiotherapy was shown to act as in situ vaccination, which can mediate systemic response to cancer in conjunction with immune checkpoint inhibitors. We aimed to investigate the DNA sensing pathways as a fundamental mechanism of immunostimulation by DNA after tumor irradiation. Key distinct DNA sensing pathways were identified in two different cell types abundant in the microenvironment of solid tumors, tumor cells and macrophages. We evaluated dose- and time-dependent expression of DNA sensors and cytokines and assayed for radiation-induced bystander effects. Understanding the timing of the activation of these pathways and subsequent cytokine expression induced by different irradiation doses could improve the treatment schemes for combining immune checkpoint inhibitors or other immunotherapies with the radiation therapy in order to improve the therapy of cancer. Therefore, this paper could complement and provide basis for current clinical studies investigating radio-immunotherapy schedules. Irradiation of tumors generates danger signals and inflammatory cytokines that promote the off-target bystander and abscopal effects, evident especially when radiotherapy is administered in combination with the immune checkpoint inhibitors (ICI). The underlying mechanisms are not fully understood; however, cGAS-STING pathway was recognized as the main mediator. In our study, we demonstrate by immunofluorescent staining that tumor cells as well as macrophages, cell types abundant in the tumor microenvironmeent (TME) accumulate DNA in their cytosol soon after irradiation. This accumulation activated several distinct DNA sensing pathways, most prominently activated DNA sensors being DDX60, DAI, and p204 in tumor cells and DDX60, DAI, p204, and RIG-I in macrophages as determined by PCR and immunofluorescence imaging studies. This was accompanied by increased expression of cytokines evaluated by flow cytometry, TNFα, and IFNβ in tumor cells and IL1β and IFNβ in macrophages, which can alter the TME and mediate off-target effects (bystander or abscopal effects). These results give insight into the mechanisms involved in the stimulation of antitumor immunity by radiation. [ABSTRACT FROM AUTHOR]