Chemokines govern leukocyte migration by attracting cells that express their cognate ligands. Many cancer types show altered chemokine secretion profiles, favoring the recruitment of pro-tumorigenic ...immune cells and preventing the accumulation of anti-tumorigenic effector cells. This can ultimately result in cancer immune evasion. The manipulation of chemokine and chemokine-receptor signaling can reshape the immunological phenotypes within the tumor microenvironment in order to increase the therapeutic efficacy of cancer immunotherapy. Here we discuss the three chemokine-chemokine receptor axes, CXCR1/2-CXCL1-3/5-8, CXCR3-CXCL9/10/11, and CXCR4-CXCL12 and their role on pro-tumorigenic immune cells and anti-tumorigenic effector cells in solid tumors. In particular, we summarize current strategies to target these axes and discuss their potential use in treatment approaches.
Cell therapy is an innovative therapeutic concept where viable cells are implanted, infused, or grafted into a patient to treat impaired or malignant tissues. The term was first introduced circa the ...19
century and has since resulted in multiple breakthroughs in different fields of medicine, such as neurology, cardiology, and oncology. Lately, cell and gene therapy are merging to provide cell products with additional or enhanced properties. In this context, adoptive transfer of genetically modified cytotoxic lymphocytes has emerged as a novel treatment option for cancer patients. To this day, five cell therapy products have been FDA approved, four of which for CD19-positive malignancies and one for B-cell maturation antigen (BCMA)-positive malignancies. These are personalized immunotherapies where patient T cells are engineered to express chimeric antigen receptors (CARs) with the aim to redirect the cells against tumor-specific antigens. CAR-T cell therapies show impressive objective response rates in clinical trials that, in certain instances, may reach up to 80%. However, the life-threatening side effects associated with T cell toxicity and the manufacturing difficulties of developing personalized therapies hamper their widespread use. Recent literature suggests that Natural Killer (NK) cells, may provide a safer alternative and an 'off-the-shelf' treatment option thanks to their potent antitumor properties and relatively short lifespan. Here, we will discuss the potential of NK cells in CAR-based therapies focusing on the applications of CAR-NK cells in cancer therapy and beyond.
Among the polypeptides that comprise the T cell receptor (TCR), only CD3ζ is found in Natural Killer (NK) cells, where it transmits signals from activating receptors such as CD16 and NKp46. NK cells ...are potent immune cells that recognize target cells through germline-encoded activating and inhibitory receptors. Genetic engineering of NK cells enables tumor-specific antigen recognition and, thus, has a significant promise in adoptive cell therapy. Ectopic expression of engineered TCR components in T cells leads to mispairing with the endogenous components, making a knockout of the endogenous TCR necessary. To circumvent the mispairing of TCRs or the need for knockout technologies, TCR complex expression has been studied in NK cells. In the current study, we explored the cellular processing of the TCR complex in NK cells. We observed that in the absence of CD3 subunits, the TCR was not expressed on the surface of NK cells and vice versa. Moreover, a progressive increase in surface expression of TCR between day three and day seven was observed after transduction. Interestingly, the TCR complex expression in NK92 cells was enhanced with a proteasome inhibitor (bortezomib) but not a lysosomal inhibitor (chloroquine). Additionally, we observed that the TCR complex was functional in NK92 cells as measured by estimating CD107a as a degranulation marker, IFNγ cytokine production, and killing assays. NK92 cells strongly degranulated when CD3ε was engaged in the presence of TCR, but not when only CD3 was overexpressed. Therefore, our findings encourage further investigation to unravel the mechanisms that prevent the surface expression of the TCR complex.
We present a sustainable and innovative model for pre-service teacher paired professional placements called the Teaching School model. The Teaching School model was piloted initially in partnership ...with a Metropolitan University and a P-12 College located in Melbourne's northern suburbs in 2013. It was expanded in 2014 to capitalise on an existing university school partnership at a regional campus of the university. We present evidence of success through the voices of pre-service teachers, mentor teachers and school principals to demonstrate the success of professional experience model. The findings clearly show the benefit of this model of professional experience for producing work-ready graduates and for creating authentic learning and teaching environments that, according to the school principals and mentor teachers, contribute to school improvement. Our research demonstrates that this Teaching School model builds relationships and creates a community of learning and teaching educators; however, its adoption is not without challenges and limitations.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent studies have reported that the quarantine imposed in several countries around the world due to Covid-19 affected the sexual function and relationship quality. On the March 23, 2020 the Greek ...government imposed a national quarantine to contain the spread of the pandemic. The impact of such conditions on sexual function and relationship quality of couples is unknown.
To investigate sexual function and relationship quality of couples during the quarantine.
An online anonymous survey was conducted one month post-impose of the quarantine, between the April 21 and the May 3, 2020. Adult respondents in a relationship completed a questionnaire including sociodemographic characteristics, structured inquiries regarding sexual activity and quality of relationship, anxiety level, and mood during the quarantine, as well as the IIEF and FSFI indices.
Sexual function was assessed using the Greek versions of the FSFI and IIEF for females and males respectively. Sexual activity using 5 statements regarding frequency of sexual thoughts, masturbation, and intercourse, quality of intercourse and general estimation of the level of sexual function. Participants graded their level of agreement. Relationship quality was assessed using 5 questions regarding communication, company, understanding, tension and general estimation of companionship. Participants graded their level of agreement. Two additional statements were used in order to evaluate mood and the level of anxiety.
A sum of 299 adult heterosexual participants in a relationship participated. Little or no negative impact on sexual function was reported. Increased anxiety and deficient mood were reported only for those with no access to their partner. Being in a steady relationship and living with their partner, but only for couples without children, resulted in satisfaction by sexual activity and enhanced emotional security.
Sexual function and relationship quality appeared as not affected by the quarantine and by the measures of social distancing. Sotiropoulou P, Ferenidou F, Owens D, et al. The Impact of Social Distancing Measures Due to COVID-19 Pandemic on Sexual Function and Relationship Quality of Couples in Greece. Sex Med 2021;9:100364.
Multiple myeloma (MM) is a type of blood cancer affecting about 2 in 100.000 people worldwide. It forms in plasma cells, the white blood cells that help our body fight infections by producing ...antibodies. Malignant plasma cells, like normal plasma cells, are found in the bone marrow. There, they proliferate at a fast pace and release large amounts of abnormal antibodies causing painful and life-threatening symptoms, such as bone damage, anemia, and kidney dysfunction. MM is most often diagnosed in people around the age of 65, and thus is commonly referred to as a disease of the elderly. MM also has a higher incidence rate in Black over Caucasian populations, and men over women.During the last decades, new treatments have significantly improved the survival of the patients, from a median of 3-4 to 8-9 years. The new treatments are based on the use of the immune system to battle cancer, hence are known as immunotherapies. Cell therapy is a type of immunotherapy. In this, immune cells with natural ability to recognize and eliminate cancer cells are taken from a small amount of patient’s or donor’s blood, processed in the laboratory and given to the patient as treatment. The ‘processing’ can be split into two main parts. First is the culture of the immune cells in order to increase their absolute number. Second is the modification of the cells with the aim to increase their anti-cancer properties. An example of this modification is the introduction of an artificial receptor, e.g. chimeric antigen receptor (CAR) or chimeric switch receptor (CSR), that targets specifically a protein found in excess on the malignant cells. Apart from their protein recognition part, CARs and CSRs have intricately designed domains, that transmit activating signals to the inside of the immune cells upon their interaction with the targeted protein. In turn, this triggers the exertion of cytotoxicity and mediates the killing of the cancer cell.In this thesis, and specifically in papers I and II, we investigated cell therapy approaches for MM based on Natural Killer (NK) cells. NK cells are part of the innate immune system, which is the body’s first defense against pathogens. They comprise 5-15% of the white blood cells in the blood circulation. Regarding cancer, NK cells hold a central place in the protection of our body. They own a unique set of mechanisms that carefully considers the health status of a cell and emits spontaneous cytotoxic activity if found abnormal. NK cell-based therapy has shown great potential in preclinical investigations and clinical trials; however, it is still not approved for broad clinical use.In paper I, we investigated the feasibility of NK cell-based therapy targeting CD38, a promising immunotherapeutic target for MM, using a CAR. CD38 is also found on NK cells, making the development of this cell therapy troublesome due to potential fratricide phenomena. We found that by applying a specific cell culture protocol, based on the addition of interleukin-2 (IL-2), CD38 on the NK cells is downregulated. This decrease, in combination with a specially designed CAR, is sufficient to overcome the challenges in the development of the cell product and shows potent CD38-directed anti-myeloma activity in our study.
Multiple myeloma (MM) is an incurable hematological cancer, in which immune checkpoint inhibition (ICI) with monoclonal antibodies (mAbs) has failed due to uncontrollable immune responses in ...combination therapies and lack of efficacy in monotherapies. Although NK cell-specific checkpoint targets such as NKG2A and KIRs are currently being evaluated in clinical trials, the clinical impact of NK cells on the PD1 cascade is less well understood compared to T cells. Furthermore, while NK cells have effector activity within the TME, under continuous ligand exposure, NK cell dysfunctionality may occur due to interaction of PD1 and its ligand PD-L1. Due to above-mentioned factors, we designed novel NK cell specific PD1-based chimeric switch receptors (PD1-CSR) by employing signaling domains of DAP10, DAP12 and CD3ζ to revert NK cell inhibition and retarget ICI. PD1-CSR modified NK cells showed increased degranulation, cytokine secretion and cytotoxicity upon recognition of PD-L1
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target cells. Additionally, PD1-CSR
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NK cells infiltrated and killed tumor spheroids. While primary NK cells (pNK), expressing native PD1, showed decreased degranulation and cytokine production against PD-L1
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target cells by twofold, PD1-CSR
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pNK cells demonstrated increased activity upon PD-L1
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target cell recognition and enhanced antibody-dependent cellular cytotoxicity. PD1-CSR
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pNK cells from patients with MM increased degranulation and cytokine expression against autologous CD138
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PD-L1
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malignant plasma cells. Taken together, the present results demonstrate that PD1-CSR
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NK cells enhance and sustain potent anti-tumor activity in a PD-L1
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microenvironment and thus represent a promising strategy to advance adoptive NK cell-based immunotherapies toward PD-L1
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cancers.
Approximately 20% of newly diagnosed multiple myeloma (NDMM) patients harbor t(11;14), a marker of inferior prognosis, resulting in up‐regulation of CCND1. These patients respond to BCL2 inhibitor ...experimental drug venetoclax. Furthermore, t(11;14) is reported to be associated with increased BCL2/MCL1 ratio. We investigated the use of venetoclax (400 mg daily) in a cohort of 25 multiple myeloma (MM) and AL‐amyloidosis patients harboring t(11;14) and assessed safety and efficacy. Efficacy was assessed by response rate (RR) and time on treatment. Furthermore, immunohistochemistry (IHC), for BCL2 family member expression was assessed at diagnosis and relapse in the venetoclax‐treated group and analyzed for correlation with clinical RR. Additionally, patient material from venetoclax non‐treated group including non‐t(11;14) diagnosis (n = 27), t(11;14) diagnosis (n = 17), t(11;14) relapse (n = 7), hyperdiploidy (n = 6) and hyperdiploidy + t(11;14) (n = 6) was used for RNA sequencing (RNASeq) and validation by qPCR. Venetoclax treatment in t(11;14) patients demonstrated manageable safety and promising efficacy. Partial responses or better were observed in eleven patients (44%). Responding patients had significantly higher BCL2/MCL1 (p = 0.031) as well as BCL2/BCL‐XL (p = 0.021) ratio, regardless of time of measurement before venetoclax treatment. Furthermore, an IRF5 motif was enriched (p < .001) in the downregulated genes in t(11;14) relapses vs diagnoses. The RR with single agent venetoclax was 71% in AL‐amyloidosis and 33% in MM, and IHC proved useful in prediction of treatment outcome. We could also demonstrate possible resistance mechanisms of t(11;14), downregulation of IRF5 targeted genes, which can be exploited for therapeutic advantages.
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