Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs.

Life-threatening 'breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS-CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals (age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, while two neutralized IFN-ω only. No patient neutralized IFN-ß. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.

Tumor Endothelial Cells (TECs) as Potential Immune Directors of the Tumor Microenvironment - New Findings and Future Perspectives.

The tumor microenvironment (TME) plays a central role in cancer development and progression. It represents a complex network of cancer cell (sub-)clones and a variety of stromal cell types. Recently, new technology platforms shed light on the cellular composition of the TME at very high resolution and identified a complex landscape of multi-lineage immune cells (e.g., T and B lymphocytes, myeloid cells, and dendritic cells), cancer associated fibroblasts (CAF) and tumor endothelial cells (TECs). A growing body of evidence suggests that metabolically, genetically and on their transcriptomic profile TECs exhibit unique phenotypic and functional characteristics when compared to normal endothelial cells (NECs). Furthermore, the functional role of TECs is multifaceted as they are not only relevant for promoting tumor angiogenesis but have also evolved as key mediators of immune regulation in the TME. Regulatory mechanisms are complex and profoundly impact peripheral immune cell trafficking into the tumor compartment by acting as major gatekeepers of cellular transmigration. Moreover, TECs are associated with T cell priming, activation and proliferation by acting as antigen-presenting cells themselves. TECs are also essential for the formation of tertiary lymphoid structures (TLS) within the tumor, which have recently been associated with treatment response to checkpoint antibody therapy. Further essential characteristics of TECs compared to NECs are their high proliferative potential as well as greatly altered gene expression profile (e.g., upregulation of pro-angiogenic, extracellular matrix remodeling, and stemness genes), which results in enhanced secretion of immunomodulatory cytokines and altered cell-surface receptors [e.g., major histocompatibility complex (MHC) and immune checkpoints]. The TEC phenotype may be rooted in an aggressive tumor micro-milieu based on cellular stress via hypoxia and reactive oxygen species (ROS). Vice versa TECs might modulate TME immunogenicity thereby fostering cancer-associated immune suppression. This review aims to elucidate the currently emergent pathophysiological aspects of TECs with a particular focus on their potential role as regulators of immune cell function in the TME. It is a main future challenge to deeply characterize the phenotypic and functional profile of TECs to illuminate their complex role within the TME. The ultimate goal is the identification of TEC-specific drug targets to improve cancer (immuno-)therapy.

Comorbidities cluster with impaired functional capacities and depressive mood and predict adverse outcome in older patients with hematological malignancies.

This study evaluates prevalence of comorbidities and their association with impairments in older patients with hematological malignancies at initial diagnosis (n = 209). At least one comorbidity was present in 62.2%, 68.5% and 93.8% as defined by CCI (Charlson Comorbidity Index), Cumulative Illness Rating Scale-Geriatric (CIRS-G) and HCT-Comorbidity Index, respectively. Severe comorbidities (CIRS-G Grade 3/4) were present in 57.9%. The mean number of affected organ systems was 3.6 (CIRS-G categories), with diabetes (18.2%), congestive heart failure and prior solid tumors (each 17.7%) detected most frequently. Comorbidities were significantly correlated with reduced functional and objective physical capacities, impaired performance and depressive mood. Both CCI and CIRS-G were found to be prognostic factors for OS (p < 0.05). CCI scoring of comorbidities, diagnosis MDS/AML and a body mass index <23kg/m2 were independent adverse predictors for OS. This first prospective analysis reveals a prognostic significance of comorbidities. Clustering of comorbidities with impairments suggests common mechanisms.

[Geriatric assessment of patients with hematological neoplasms]. / Geriatrisches Assessment bei Patienten mit hämatologischen Neoplasien.

Hematological malignancies are typical diseases of the elderly. The aging of the population in the Western World results in a significant increase in the number of elderly patients with hematological malignant diseases. This has important consequences for medicine. One consequence of this development is that the need for tools for the evaluation of both functional and global status of the elderly increases. The use of these tools enables the hematologist to better stratify the patients, to individualize therapy better, to possibly modify therapy in order to improve implementation of supportive measures and interventions, to minimize toxicity and side effects and ultimately to tailor the treatment to the individual patient. Several tools are available for geriatric assessment (GA) and there is strong evidence that an effective GA can detect previously unknown problems. The targeted intervention improves the prognosis and compliance of therapy in elderly patients with hematological malignant diseases.