UNASSIGNED: Effective treatments for the ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are limited. The virus has evolved strategies to evade the immune system or hijack immune responses to facilitate infection and escape immune surveillance. Mechanistically, SARS-CoV-2 takes advantage of TLR4 and cytokine-induced integrins to promote its entrance into the cell. Furthermore, the activation of pattern recognition receptors (PRR)-mediated signaling pathways is compromised by SARS-CoV-2 non-structural proteins (NSPs), accessory protein open reading frames (ORFs), and structural proteins upon infection, contributing to viral infection and replication. Host factors necessary for cellular protein synthesis, metabolism, and viral replication can also be inhibited by the SARS-CoV-2 proteins. Exploring specific mechanisms would optimize the therapy methods and benefit drug research and development.
UNASSIGNED: We describe pathways and mechanisms by which SARS-CoV-2 evades immune system; these include the mechanisms that operate during virus entry, signaling pathways involved, and processes at RNA and protein levels.
UNASSIGNED: Increased understanding of how viruses interfere with immune responses would provide more evidence for drug development. Drugs targeting conserved viral proteins to inhibit their replication or host factors to enhance immune responses would minimize the impact of virus mutations and prepare for future coronavirus outbreaks.

OBJECTIVE: Natural Killer (NK) cells are a vital part of immune surveillance and have been implicated in colorectal cancer development and prognosis. This systematic review aims to distil the literature on NK cells as it relates to colorectal cancer.
METHODS: All published studies over 10 years relating to NK cells and colorectal cancer were reviewed. All studies publishing in English, searchable via pubmed or through reference review and reporting directly on the nature or function of NK cells in colorectal cancer patients were included. Outcomes were determined as alterations or new information regarding NK cells in colorectal cancer patients.
RESULTS: Natural killer cells may be implicated in the development of colorectal cancer and may play a role in prognostication of the disease. NK cells are altered by the treatment (both surgical and medical) of colorectal cancer and it seems likely that they will also be a target for manipulation to improve colorectal cancer survival.
CONCLUSIONS: NK cell morphology and function are significantly affected by the development of colorectal cancer. Observation of NK cell changes may lead to earlier detection and better prognostication in colorectal cancer. Further study is needed into immunological manipulation of NK cells which may lead to improved colorectal cancer survival.

Natural killer (NK) cells lead immune surveillance against cancer and early elimination of small tumors. Owing to their ability to engage tumor targets without the need of specific antigen, the therapeutic potential of NK cells has been extensively explored in hematological malignancies. In solid tumors, however, their role in the clinical arena remains poorly exploited despite a broad accumulation of preclinical data. In this article, we review our current knowledge of NK cells\' biology, and highlight the challenges facing NK cell antitumor strategies in solid tumors. We further summarize the abundant preclinical attempts at overcoming these challenges, present past and ongoing clinical trial data and finally discuss the potential impact of novel insights on the development of NK cell-based therapies.

Immunopolymorphism is considered as an important aspect behind the resistance or susceptibility of the host to an infectious disease. Over the years, researchers have explored many genetic factors for their role in immune surveillance against infectious diseases. Polymorphic characters in the gene encoding Toll-like receptors (TLRs) play profound roles in inducing differential immune responses by the host against parasitic infections. Protein(s) encoded by TLR gene(s) are immensely important due to their ability of recognizing different types of pathogen associated molecular patterns (PAMPs). This study reviews the polymorphic residues present in the nucleotide or in the amino acid sequence of TLRs and their influence on alteration of inflammatory signalling pathways promoting either susceptibility or resistance to major infectious diseases, including tuberculosis, leishmaniasis, malaria and filariasis. Population-based studies exploring TLR polymorphisms in humans are primarily emphasized to discuss the association of the polymorphic residues with the occurrence and epidemiology of the mentioned infectious diseases. Principal polymorphic residues in TLRs influencing immunity to infection are mostly single nucleotide polymorphisms (SNPs). I602S (TLR1), R677W (TLR2), P554S (TLR3), D299G (TLR4), F616L (TLR5), S249P (TLR6), Q11L (TLR7), M1V (TLR8), G1174A (TLR9) and G1031T (TLR10) are presented as the major influential SNPs in shaping immunity to pathogenic infections. The contribution of these SNPs in the structure-function relationship of TLRs is yet not clear. Therefore, molecular studies on such polymorphisms can improve our understanding on the genetic basis of the immune response and pave the way for therapeutic intervention in a more feasible way.

Prostate cancer treatment is currently based on surgical removal, radiotherapy, and hormone therapy. In recent years, another therapeutic method has emerged-immunological treatment. Immunotherapy modulates and strengthens one\'s immune responses against cancer. Neoplastic cells naturally escape from the control of the immune system, and the main goal of immune therapy is to bring the control back. Satisfying outcomes after treatment of advanced melanoma and lung cancer suggest a great potential of immunotherapy as an approach for other tumors\' treatment, especially in patients primarily introduced to palliative care. After initial clinical trials, immunotherapy seems to have different side effects than chemotherapy. Prostate cancer was the first neoplasm in which a specific vaccine significantly improved survival. There is a tremendous potential for synergistic combinations of immunotherapy with conventional cancer treatments. A combination of several drugs or methods can be a key in radical treatment of metastatic prostate cancer as demonstrated by preliminary studies.

BACKGROUND: Lynch syndrome (HNPCC, hereditary non-polyposis colorectal cancer) is a syndrome of predisposition to cancer inherited in an autosomal dominant fashion. A person with Lynch syndrome has a considerably increased risk of colorectal cancer in comparison with the general population.
METHODS: We present a case of a 24-year-old man with Lynch syndrome (carrying an MLH1 gene mutation) who had colorectal adenocarcinoma diagnosed at 16 years of age. During this time, he had a colectomy performed and chemotherapy was administered (5-FU, CDDP, Leucovorin). Due to hepatic metastases, a decision was made to change chemotherapy to IF with ADM, as a result of which complete remission was obtained. However, kidney failure developed. Its cause was not fully elucidated. The patient was treated by hemodialyses. After six years of complete remission of cancer, kidney transplantation started to be considered. Before the patient was found eligible for transplantation, extended diagnostic tests were performed: whole body PET scan, tumour marker tests and intestinal endoscopy, which did not reveal any abnormalities. The patient had a family donor (mother) who had no contraindications to kidney donation. Kidney transplantation was performed on 15/10/2012. Induction with basiliximab was used, along with steroids, tacrolimus, and mycophenolate mofetil was also administered. Three months after the procedure CNI/mTOR conversion was performed. The maintenance treatment includes prednisone, everolimus and mycophenolate mofetil. One year after transplantation, renal function is normal. The patient is subjected to close oncological surveillance.
CONCLUSIONS: The risk of recurrence or new development of cancer related to immunosuppressive treatment should be considered on a case-by-case basis. In patients with a history or high risk of cancer, immunosuppression protocols based on the m-TOR pathway inhibitors should be used, if possible. Oncological surveillance and early detection of new cancer lesions are also important.

Natural Killer (NK) cells are important players of the innate arm of the immune system and provide an early defense against pathogens and tumor-transformed cells. Peripheral blood NK (PB-NK) cells were first identified because of their ability to spontaneously kill tumor-cell targets in vitro without the need for specific antigen priming, which is the reason that they were named \'natural killer\' cells. The characterization of NK cells in human tissues and body organs represented another important step forward to better understand their physiology and physiopathology. In this regard, many reports revealed over the past decade a differential anatomic distribution of NK cell subsets in several sites such as the intestine, lung, cervix, placenta and liver as well as in secondary lymphoid organs such as spleen, lymph nodes and tonsils. Among all these tissues, the liver is certainly unique as its parenchyma contains an unusually high number of infiltrating immune cells with 30-50% of total lymphocytes being NK cells. Given the constant liver intake of non-self antigens from the gastrointestinal tract via the portal vein, hepatic NK (H-NK) cells must retain a certain degree of tolerance in the context of their immune-surveillance against dangers to the host. Indeed, the breakdown of the tolerogenic state of the liver-associated immune system has been shown to induce autoimmunity. However, the role of NK cells during the course of autoimmune liver diseases is still being debated mainly because a complete characterization of H-NK cells normally resident in healthy human liver has not yet been fully disclosed. Furthermore, the differences in phenotype and functions between human and mouse H-NK cells often preclude translation of results obtained from murine models into experimental approaches to be performed in humans. Here, we provide an extensive characterization of the phenotype of H-NK cells physiologically resident in the human liver by both mentioning data available in literature and including a set of original results recently developed in our laboratory. We then review our current knowledge in regard to the contribution of H-NK cells in regulating local immune homeostasis and tolerance as well as in inducing the development of liver autoimmunity.

Cancer is one of the most important pathological conditions facing mankind in the 21st century, and is likely to become the most important cause of death as improvements continue in health, diet and life expectancy. The immune response is responsible for controlling nascent cancer through immunosurveillance. If tumours escape this control, they can develop into clinical cancer. Although surgery and chemo- or radiotherapy have improved survival rates significantly, there is a drive to reharness immune responses to treat disease. As T cells are one of the key immune cells in controlling cancer, research is under way to enhance their function and improve tumour targeting. This can be achieved by transduction with tumour-specific T cell receptor (TCR) or chimaeric antigen receptors (CAR) to generate redirected T cells. Virus-specific cells can also be transduced with TCR or CAR to create bi-functional T cells with specificity for both virus and tumour. In this review we outline the development and optimization of redirected and bi-functional T cells, and outline the results from current clinical trials using these cells. From this we discuss the challenges involved in generating effective anti-tumour responses while avoiding concomitant damage to normal tissues and organs.

The immune system has been reported to suppress the development and progression of neoplastic lesions; however, the exact mechanisms by which neoplastic lesions and the immune system interact are not well understood. Within the last decade, tiny membrane bound particles, approximately 30-100 nm in diameter, have been observed in the blood and other body fluids. These particles, currently called exosomes, are released from many types of tissues including tumors, and they contain and carry many proteins, and mRNAs and microRNA species. We review here how tumors suppress the immune system, especially by the formation of exosomes. Exosomes released from tumors are carried in part by the vascular system to distant cells, which phagocytose them. Depending on the proteins, mRNAs or microRNAs in the exosomes and the cell type, phagocytosis of exosomes may provide a modulating signal to the cell. In the case of exosomes from tumors, uptake of the exosomes by cells of the immune system has been reported to have three main effects: 1) suppression of the number and activity of natural killer cells, 2) suppression of the activity of T cells and 3) suppression of the number and maturation of mature dendritic cells.

Many immunosuppressive drugs are associated with an increased risk of B-cell lymphoma, squamous cell carcinoma, and Kaposi sarcoma. Thirteen immunosuppressive drugs have been tested in 2-year carcinogenicity studies (abatacept; azathioprine; busulfan; cyclophosphamide; cyclosporine; dexamethasone; everolimus; leflunomide; methotrexate; mycophenolate mofetil; prednisone; sirolimus; and tacrolimus) and in additional models including neonatal and genetically modified mice; chemical, viral, ultraviolet, and ionizing radiation co-carcinogenesis, and in models with transplanted tumor cells. The purpose of this review is to outline the mechanisms by which immunosuppressive drugs can influence neoplasia, to summarize the available preclinical data on the 13 drugs, and to critically review the performance of the models. A combination of primary tumor and metastasis assays conducted with transplanted cells may provide the highest value for hazard identification and can be applied on a case-by-case basis. However, for both small molecules and therapeutic proteins, determining the relative risk to patients from preclinical data remains problematic. Classifying immunosuppressive drugs based on their mechanism of action and hazard identification from preclinical studies and a prospective pharmacovigilance program to monitor carcinogenic risk may be a feasible way to manage patient safety during the clinical development program and postmarketing.