New insights into the pathophysiology and therapeutic targets of asthma and comorbid chronic rhinosinusitis with or without nasal polyposis

Asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) or without (CRSsNP) are chronic respiratory diseases. These two disorders often co-exist based on common anatomical, immunological, histopathological, and pathophysiological basis. Usually, asthma with comorbid CRSwNP is driven by type 2 (T2) inflammation which predisposes to more severe, often intractable, disease. In the past two decades, innovative technologies and detection techniques in combination with newly introduced targeted therapies helped shape our understanding of the immunological pathways underlying inflammatory airway diseases and to further identify several distinct clinical and inflammatory subsets to enhance the development of more effective personalized treatments. Presently, a number of targeted biologics has shown clinical efficacy in patients with refractory T2 airway inflammation, including anti-IgE (omalizumab), anti-IL-5 (mepolizumab, reslizumab)/anti-IL5R (benralizumab), anti-IL-4R-α (anti-IL-4/IL-13, dupilumab), and anti-TSLP (tezepelumab). In non-type-2 endotypes, no targeted biologics have consistently shown clinical efficacy so far. Presently, multiple therapeutical targets are being explored including cytokines, membrane molecules and intracellular signalling pathways to further expand current treatment options for severe asthma with and without comorbid CRSwNP. In this review, we discuss existing biologics, those under development and share some views on new horizons.</p

M1/M2 macrophages and their overlaps – myth or reality?

Macrophages represent heterogeneous cell population with important roles in defence mechanisms and in homoeostasis. Tissue macrophages from diverse anatomical locations adopt distinct activation states. M1 and M2 macrophages are two polarized forms of mononuclear phagocyte in vitro differentiation with distinct phenotypic patterns and functional properties, but in vivo, there is a wide range of different macrophage phenotypes in between depending on the microenvironment and natural signals they receive. In human infections, pathogens use different strategies to combat macrophages and these strategies include shaping the macrophage polarization towards one or another phenotype. Macrophages infiltrating the tumours can affect the patient’s prognosis. M2 macrophages have been shown to promote tumour growth, while M1 macrophages provide both tumour-promoting and anti-tumour properties. In autoimmune diseases, both prolonged M1 activation, as well as altered M2 function can contribute to their onset and activity. In human atherosclerotic lesions, macrophages expressing both M1 and M2 profiles have been detected as one of the potential factors affecting occurrence of cardiovascular diseases. In allergic inflammation, T2 cytokines drive macrophage polarization towards M2 profiles, which promote airway inflammation and remodelling. M1 macrophages in transplantations seem to contribute to acute rejection, while M2 macrophages promote the fibrosis of the graft. The view of pro-inflammatory M1 macrophages and M2 macrophages suppressing inflammation seems to be an oversimplification because these cells exploit very high level of plasticity and represent a large scale of different immunophenotypes with overlapping properties. In this respect, it would be more precise to describe macrophages as M1-like and M2-like

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

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

How COVID-19 Affects Lung Transplantation: A Comprehensive Review

Lung transplant (LuTx) recipients are at a higher risk of developing serious illnesses from COVID-19, and thus, we have closely reviewed the consequences of the COVID-19 pandemic on lung transplantation. In most transplant centers, the overall LuTx activity significantly declined and led to a specific period of restricting lung transplantation to urgent cases. Moreover, several transplant centers reported difficulties due to the shortage of ICU capacities. The fear of donor-derived transmission generated extensive screening programs. Nevertheless, reasonable concerns about the unnecessary losses of viable organs were also raised. The overall donor shortage resulted in increased waiting-list mortality, and COVID-19-associated ARDS became an indication of lung transplantation. The impact of specific immunosuppressive agents on the severity of COVID-19 varied. Corticosteroid discontinuation was not found to be beneficial for LuTx patients. Tacrolimus concentrations were reported to increase during the SARS-CoV-2 infection, and in combination with remdesivir, tacrolimus may clinically impact renal functions. Monoclonal antibodies were shown to reduce the risk of hospitalization in SOT recipients. However, understanding the pharmacological interactions between the anti-COVID-19 drugs and the immunosuppressive drugs requires further research

Patient with composite haemangioendothelioma containing angiosarcoma-like areas in the setting of congenital lymphoedema mimicking Stewart-Treves syndrome: a case report

Abstract Background Composite haemangioendothelioma is a rare vascular neoplasm with indolent to intermediate malignant potential. Diagnosis of this disease relays on histopathological identification of at least two different morphologically distinctive vascular components in proper clinical settings. Exceedingly rare cases of this neoplasm can exhibit areas resembling high-grade angiosarcoma, which does not change the biological behaviour. Such lesions tend to occur in the setting of chronic lymphoedema and thus, can mimic Stewart-Treves syndrome, which has a much worse clinical outcome and prognosis. Case presentation We present a case of 49 years old male suffering from chronic lymphoedema of the left lower extremity who had developed a composite haemangioendothelioma with high grade angiosarcoma-like areas mimicking the Stewart-Treves syndrome. Given the multifocality of the disease, the only potentially curable surgical treatment would be hemipelvectomy, which was refused by the patient. The patient has been followed-up, with no signs of local progression of the remaining disease, nor a distant spread outside the involved extremity for two years. Conclusions Composite haemangioendothelioma represents a rare malignant vascular tumour, with significantly more favourable biological behaviour than angiosarcoma, even in cases where angiosarcoma-like areas are present. For that reason, composite haemangioendothelioma can be easily misdiagnosed as true angiosarcoma. The rarity of this disease unfortunately hampers the development of clinical practice guidelines and the implementation of treatment recommendations. Most of the patients with localized tumour are treated by wide surgical resection, without neo- or adjuvant radiotherapy or chemotherapy. However, in the case of this diagnosis, the watch-and-wait approach is better than mutilating procedure, highlighting the necessity of establishing of the correct diagnosis

Fas-Fas Ligand Interplay in the Periphery of Salivary Gland Carcinomas as a New Checkpoint Predictor for Disease Severity and Immunotherapy Response

Salivary gland carcinomas (SGCs) are extremely morphologically heterogeneous, and treatment options for this disease are limited. Immunotherapy with immune checkpoint inhibitors (ICIs) represents a revolutionary treatment approach. However, SGCs remain largely resistant to this therapy. An increasing body of evidence suggests that resistance to ICI therapy is modulated by the Fas (CD95)–Fas ligand (FasL, CD178) interplay between tumor cells and immune cells. In this study, we examined the Fas–FasL interplay between tumor cells and tumor-infiltrating immune cells (TIICs) in the center and periphery of SGCs from 62 patients. We found that the Fas-expressing tumor cells accumulated in the center of SGC tumors with increasing tumor stage. Furthermore, this accumulation occurred regardless of the presence of TIICs expressing high levels of FasL. On the contrary, a loss of Fas-expressing TIICs with increasing tumor stage was found in the tumor periphery, whereas FasL expression in tumor cells in the tumor periphery correlated with tumor stage. These data suggest that SGC cells are resistant to FasL-induced apoptosis by TIICs but could utilize FasL to eliminate these cells in high-stage tumors to provide resistance to immunotherapy