Rictor beyond the TORC: linking the proliferation, migration and Fc?RI-mediated degranulation of human mast cells

Rictor is a cytosolic protein that was originally recognized as a specific component of the mammalian target of rapamycin (mTOR) complex 2 (mTORC2). This complex integrates nutrient- and growth factor-induced signaling cascades to regulate cell proliferation and metabolism. An increasing body of evidence however shows that rictor may also function independently of mTORC2 through association with other proteins and complexes. Recent studies on mast cells demonstrated that in the context of mTORC2 rictor positively regulates proliferation of immature and migration of mature mast cells whereas by itself rictor independently functions as a molecular relay that sets the sensitivity of high affinity receptor for IgE (FceRI) for activating mast cell degranulation. These novel findings suggest that rictor is a multifunctional protein that plays a role in synchronization of multiple cellular functions in mast cells

The expression profiles of CD47 in the tumor microenvironment of salivary gland cancers: a next step in histology-driven immunotherapy

Background: Salivary gland carcinomas (SGC) are extremely rare malignancies with only limited treatment options for the metastatic phase of the disease. Treatment with anti-CD47 antibodies could represent a potent therapy for SGCs by promoting the phagocytic clearance of tumor cells through various mechanisms. However, the efficacy of anti-CD47 therapy is largely dependent on the expression of CD47 within the tumor microenvironment (TME). Materials and Methods: In 43 patients with SGC, we were the first to investigate the CD47 expression in both tumor cells and tumor-infiltrating immune cells (TIIC) in the center and periphery of primary tumors. We also correlated the data with the clinicopathological variables of the patients and offered novel insights into the potential effectiveness of anti-CD47 therapy in SGCs. Results: We observed that the CD47+ tumor cells are outnumbered by CD47+ TIICs in mucoepidermoid carcinoma. In the tumor center, the proportion of CD47+ tumor cells was comparable to the proportion of CD47+ TIICs in most histological subtypes. In low-grade tumors, significantly higher expression of CD47 was observed in TIICs in the periphery of the tumor as compared to the center of the tumor. Conclusion: The reason for a high expression of ‘don’t eat me’ signals in TIICs in the tumor periphery is unclear. However, we hypothesize that in the tumor periphery, upregulation of CD47 in TIICs could be a mechanism to protect newly recruited leukocytes from macrophage-mediated phagocytosis, while also allowing the removal of old or exhausted leukocytes in the tumor center

Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Defining the critical hurdles in cancer immunotherapy

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer

Diagnosticke a patogeneticke aspekty autoprotilatek proti cytoplasmatickym antigenum neutrofilnich leukocytu.

Antineutrophil cytoplasmic autoantibodies (ANCA) represent a heterogenous group of autoantibodies reacting with components of primary granules of polymorphonuclear leukocytes (PMN). Determination of the presence and type of ANCA became recently a part of routine diagnostic methods, which contribute to the laboratory diagnostics of systemic vasculitis, namely Wegener's granulomatosis. However, ANCA occur also in other diseases in which the significance is less clear. Several mechanisms by which ANCA may be involved in the pathogenesis of tissue damage were described. This dissertation thesis includes comments to the articles published already in Czech and international journals and contains full-text of articles prepared for publication. The unifying theme of these articles are antineutrophil cytoplasmic antibodies and vasculitis. Clinically oriented articles deal with diagnostic and therapeutic aspects of ANCA and associated diseases in childhood as well as in adulthood. Experimental works are concentrated on pathogenic mechanisms of ANCA action, namely to the influence of bactericidal mechanisms of PMN, the influence of apoptosis and the evaluation of cytokines and adhesion molecules in ANCA-associated diseases.Available from STL Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi

Rictor beyond the TORC: linking the proliferation, migration and FcεRI-mediated degranulation of human mast cells

Rictor is a cytosolic protein that was originally recognized as a specific component of the mammalian target of rapamycin (mTOR) complex 2 (mTORC2). This complex integrates nutrient- and growth factor-induced signaling cascades to regulate cell proliferation and metabolism. An increasing body of evidence however shows that rictor may also function independently of mTORC2 through association with other proteins and complexes. Recent studies on mast cells demonstrated that in the context of mTORC2 rictor positively regulates proliferation of immature and migration of mature mast cells whereas by itself rictor independently functions as a molecular relay that sets the sensitivity of high affinity receptor for IgE (FceRI) for activating mast cell degranulation. These novel findings suggest that rictor is a multifunctional protein that plays a role in synchronization of multiple cellular functions in mast cells

Clinical Outcome of Coronavirus Disease 2019 in Patients with Primary Antibody Deficiencies

In 2019, the novel coronavirus, SARS-CoV-2, caused a worldwide pandemic, affecting more than 630 million individuals and causing 6.5 million deaths. In the general population, poorer outcomes have been associated with older age, chronic lung and cardiovascular diseases, and lymphopenia, highlighting the important role of cellular immunity in the immune response against SARS-CoV-2. Moreover, SARS-CoV-2 variants may have a significant impact on disease severity. There is a significant overlap with complications commonly found in inborn errors of immunity (IEI), such as primary antibody deficiencies. The results of various studies have provided ambiguous findings. Several studies identified risk factors in the general population with a minor impact on SARS-CoV-2 infection. However, other studies have found a significant contribution of underlying immunodeficiency and immune-system dysregulation to the disease course. This ambiguity probably reflects the demographic differences and viral evolution. Impaired antibody production was associated with prolonged viral shedding, suggesting a critical role of humoral immunity in controlling SARS-CoV-2 infection. This may explain the poorer outcomes in primary antibody deficiencies compared to other IEIs. Understanding coronavirus disease 2019 (COVID-19) pathogenesis and identifying risk factors may help us identify patients at high risk of severe COVID-19 for whom preventive measures should be introduced

Thapsigargin-Stimulated LAD2 Human Mast Cell Line Is a Potent Cellular Adjuvant for the Maturation of Monocyte-Derived Dendritic Cells for Adoptive Cellular Immunotherapy

The preparation of dendritic cells (DCs) for adoptive cellular immunotherapy (ACI) requires the maturation of ex vivo-produced immature(i) DCs. This maturation ensures that the antigen presentation triggers an immune response towards the antigen-expressing cells. Although there is a large number of maturation agents capable of inducing strong DC maturation, there is still only a very limited number of these agents approved for use in the production of DCs for ACI. In seeking novel DC maturation agents, we used differentially activated human mast cell (MC) line LAD2 as a cellular adjuvant to elicit or modulate the maturation of ex vivo-produced monocyte-derived iDCs. We found that co-culture of iDCs with differentially activated LAD2 MCs in serum-containing media significantly modulated polyinosinic:polycytidylic acid (poly I:C)-elicited DC maturation as determined through the surface expression of the maturation markers CD80, CD83, CD86, and human leukocyte antigen(HLA)-DR. Once iDCs were generated in serum-free conditions, they became refractory to the maturation with poly I:C, and the LAD2 MC modulatory potential was minimized. However, the maturation-refractory phenotype of the serum-free generated iDCs was largely overcome by co-culture with thapsigargin-stimulated LAD2 MCs. Our data suggest that differentially stimulated mast cells could be novel and highly potent cellular adjuvants for the maturation of DCs for ACI

Novel Insights into the Immunotherapy of Soft Tissue Sarcomas: Do We Need a Change of Perspective?

Soft tissue sarcomas (STSs) are rare mesenchymal tumors. With more than 80 histological subtypes of STSs, data regarding novel biomarkers of strong prognostic and therapeutic value are very limited. To date, the most important prognostic factor is the tumor grade, and approximately 50% of patients that are diagnosed with high-grade STSs die of metastatic disease within five years. Systemic chemotherapy represents the mainstay of metastatic STSs treatment for decades but induces response in only 15–35% of the patients, irrespective of the histological subtype. In the era of immunotherapy, deciphering the immune cell signatures within the STSs tumors may discriminate immunotherapy responders from non-responders and different immunotherapeutic approaches could be combined based on the predominant cell subpopulations infiltrating the STS tumors. Furthermore, understanding the immune diversity of the STS tumor microenvironment (TME) in different histological subtypes may provide a rationale for stratifying patients according to the TME immune parameters. In this review, we introduce the most important immune cell types infiltrating the STSs tumors and discuss different immunotherapies, as well as promising clinical trials, that would target these immune cells to enhance the antitumor immune responses and improve the prognosis of metastatic STSs patients

LL-37 as a Powerful Molecular Tool for Boosting the Performance of Ex Vivo-Produced Human Dendritic Cells for Cancer Immunotherapy

Ex vivo-produced dendritic cells (DCs) constitute the core of active cellular immunotherapy (ACI) for cancer treatment. After many disappointments in clinical trials, the current protocols for their preparation are attempting to boost their therapeutic efficacy by enhancing their functionality towards Th1 response and capability to induce the expansion of cytotoxic tumor-specific CD8+ T cells. LL-37 is an antimicrobial peptide with strong immunomodulatory potential. This potential was previously found to either enhance or suppress the desired anti-tumor DC functionality when used at different phases of their ex vivo production. In this work, we show that LL-37 can be implemented during the whole process of DC production in a way that allows LL-37 to enhance the anti-tumor functionality of produced DCs. We found that the supplementation of LL-37 during the differentiation of monocyte-derived DCs showed only a tendency to enhance their in vitro-induced lymphocyte enrichment with CD8+ T cells. The supplementation of LL-37 also during the process of DC antigen loading (pulsation) and maturation significantly enhanced the cell culture enrichment with CD8+ T cells. Moreover, this enrichment was also associated with the downregulated expression of PD-1 in CD8+ T cells, significantly higher frequency of tumor cell-reactive CD8+ T cells, and superior in vitro cytotoxicity against tumor cells. These data showed that LL-37 implementation into the whole process of the ex vivo production of DCs could significantly boost their anti-tumor performance in ACI