Autoimmune complications in chronic lymphocytic leukemia in the era of targeted drugs

Autoimmune phenomena are frequently observed in patients with chronic lymphocytic leukemia (CLL) and are mainly attributable to underlying dysfunctions of the immune system. Autoimmune cytopenias (AIC) affect 4–7% of patients with CLL and mainly consist of autoimmune hemolytic anemia and immune thrombocytopenia. Although less common, non-hematological autoimmune manifestations have also been reported. Treatment of CLL associated AIC should be primarily directed against the autoimmune phenomenon, and CLL specific therapy should be reserved to refractory cases or patients with additional signs of disease progression. New targeted drugs (ibrutinib, idelalisib and venetoclax) recently entered the therapeutic armamentarium of CLL, showing excellent results in terms of efficacy and became an alternative option to standard chemoimmunotherapy for the management of CLL associated AIC. However, the possible role of these drugs in inducing or exacerbating autoimmune phenomena still needs to be elucidated. In this article, we review currently available data concerning autoimmune phenomena in patients with CLL, particularly focusing on patients treated with ibrutinib, idelalisib, or venetoclax, and we discuss the possible role of these agents in the management of AIC

Immune dysfunctions and immune-based therapeutic interventions in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a wide range of tumor-induced alterations, which affect both the innate and adaptive arms of the immune response, and accumulate during disease progression. In recent years, the development of targeted therapies, such as the B-cell receptor signaling inhibitors and the Bcl-2 protein inhibitor venetoclax, has dramatically changed the treatment landscape of CLL. Despite their remarkable anti-tumor activity, targeted agents have some limitations, which include the development of drug resistance mechanisms and the inferior efficacy observed in high-risk patients. Therefore, additional treatments are necessary to obtain deeper responses and overcome drug resistance. Allogeneic hematopoietic stem cell transplantation (HSCT), which exploits immune-mediated graft-versus-leukemia effect to eradicate tumor cells, currently represents the only potentially curative therapeutic option for CLL patients. However, due to its potential toxicities, HSCT can be offered only to a restricted number of younger and fit patients. The growing understanding of the complex interplay between tumor cells and the immune system, which is responsible for immune escape mechanisms and tumor progression, has paved the way for the development of novel immune-based strategies. Despite promising preclinical observations, results from pilot clinical studies exploring the safety and efficacy of novel immune-based therapies have been sometimes suboptimal in terms of long-term tumor control. Therefore, further advances to improve their efficacy are needed. In this context, possible approaches include an earlier timing of immunotherapy within the treatment sequencing, as well as the possibility to improve the efficacy of immunotherapeutic agents by administering them in combination with other anti-tumor drugs. In this review, we will provide a comprehensive overview of main immune defects affecting patients with CLL, also describing the complex networks leading to immune evasion and tumor progression. From the therapeutic standpoint, we will go through the evolution of immune-based therapeutic approaches over time, including i) agents with broad immunomodulatory effects, such as immunomodulatory drugs, ii) currently approved and next-generation monoclonal antibodies, and iii) immunotherapeutic strategies aiming at activating or administering immune effector cells specifically targeting leukemic cells (e.g. bi-or tri-specific antibodies, tumor vaccines, chimeric antigen receptor T cells, and checkpoint inhibitors)

Impact of immune parameters and immune dysfunctions on the prognosis of patients with chronic lymphocytic leukemia

SIMPLE SUMMARY: In chronic lymphocytic leukemia (CLL), immune alterations—affecting both the innate and adaptive immunity—are very common. As a clinical consequence, patients with CLL frequently present with autoimmune phenomena, increased risk of infections and second malignancies. The aim of this review article is to present available data on CLL-associated alterations of immune parameters that correlate with known prognostic markers and with clinical outcome. Also, data on the impact of immune-related clinical manifestations on the prognosis of patients with CLL will be discussed. ABSTRACT: Chronic lymphocytic leukemia (CLL) is characterized by a wide spectrum of immune alterations, affecting both the innate and adaptive immunity. These immune dysfunctions strongly impact the immune surveillance, facilitate tumor progression and eventually affect the disease course. Quantitative and functional alterations involving conventional T cells, γδ T cells, regulatory T cells, NK and NKT cells, and myeloid cells, together with hypogammaglobulinemia, aberrations in the complement pathways and altered cytokine signature have been reported in patients with CLL. Some of these immune parameters have been shown to associate with other CLL-related characteristics with a known prognostic relevance or to correlate with disease prognosis. Also, in CLL, the complex immune response dysfunctions eventually translate in clinical manifestations, including autoimmune phenomena, increased risk of infections and second malignancies. These clinical issues are overall the most common complications that affect the course and management of CLL, and they also may impact overall disease prognosis

Impact of immune parameters and immune dysfunctions on the prognosis of patients with chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is characterized by a wide spectrum of immune alterations, affecting both the innate and adaptive immunity. These immune dysfunctions strongly impact the immune surveillance, facilitate tumor progression and eventually affect the disease course. Quantitative and functional alterations involving conventional T cells, γδ T cells, regulatory T cells, NK and NKT cells, and myeloid cells, together with hypogammaglobulinemia, aberrations in the complement pathways and altered cytokine signature have been reported in patients with CLL. Some of these immune parameters have been shown to associate with other CLL‐related characteristics with a known prognostic relevance or to correlate with disease prognosis. Also, in CLL, the complex immune response dysfunctions eventually translate in clinical manifestations, including autoimmune phenomena, increased risk of infections and second malignancies. These clinical issues are overall the most common complications that affect the course and management of CLL, and they also may impact overall disease prognosis

Inter-individual differences in foraging tactics of a colonial raptor : consistency, weather effects, and fitness correlates

Background: Consistent inter-individual differences in behavioural phenotypes may entail differences in energy efficiency and expenditure, with different fitness payoffs. In colonial-breeding species, inter-individual differences in foraging behaviour may evolve to reduce resource use overlap among conspecifics exploiting shared foraging areas. Furthermore, individual differences in foraging behaviour may covary with individual characteristics, such as sex or physiological conditions. Methods: We investigated individual differences in foraging tactics of a colonial raptor, the lesser kestrel (Falco naumanni). We tracked foraging trips of breeding individuals using miniaturized biologgers. We classified behaviours from GPS data and identified tactics at the foraging trip level by cluster analysis. We then estimated energy expenditure associated to each tactic from tri-axial accelerometer data. Results: We obtained 489 foraging trips by 36 individuals. Two clusters of trips were identified, one (SF) characterized by more static foraging behaviour and the other (DF) by more dynamic foraging behaviour, with a higher proportion of flying activity and a higher energy expenditure compared to SF. Lesser kestrels showed consistent inter-individual differences in foraging tactics across weather condition gradients, favouring DF trips as solar radiation and crosswind intensity increased. DF trips were more frequent during the nestling-rearing than during the egg incubation stage. Nestlings whose tracked parent was more prone to perform DF trips experienced higher daily mass increase, irrespective of nestling feeding rates. Conclusions: Our study provided evidence that breeding lesser kestrels flexibly adopted different foraging tactics according to contingent weather landscapes, with birds showing consistent inter-individual differences in the tendency to adopt a given tactic. The positive correlation between the tendency to perform more energy-demanding DF trips and nestling growth suggests that individual differences in foraging behaviour may play a role in maintaining key life-history trade-offs between reproduction and self-maintenance

HST astrometry of the closest Brown Dwarfs -- II. Improved parameters and constraints on a third body

Located at less than 2pc away, Luhman16AB (WISE.J104915.57-531906.1) is the closest pair of brown dwarfs and third closest `stellar' system to Earth. An exoplanet candidate in the Luhman16 binary system was reported in 2017 based on a weak astrometric signature in the analysis of 12 HST epochs. An additional epoch collected in 2018 and re-analysis of the data with more advanced methods further increased the significance level of the candidate, consistent with a Neptune-mass exoplanet orbiting one of the Luhman16 brown dwarf components. We report the joint analysis of these previous data together with two new astrometric HST epochs we obtained to confirm or disprove this astrometric signature. Our new analysis rules out presence of a planet orbiting one component of the Luhman16AB system for masses M > 1.5 M_Nep (Neptune masses) and periods between 400 and 5000 days. However, the presence of third bodies with masses M < 3 M_Nep and periods between 2 and 400 days (~1.1yrs) can not be excluded. Our measurements make significant improvements to the characterization of this sub-stellar binary, including its mass-ratio 0.8305+/-0.0006, individual component masses 35.4+/-0.2 M_Jup and 29.4+/-0.2 M_Jup (Jupiter masses), and parallax distance 1.9960pc +/- 50AU. Comparison of the masses and luminosities of Luhman16AB to several evolutionary models shows persistent discrepancies in the ages of the two components, but strengthens the case that this system is a member of the 510+/-95 Myr Oceanus Moving Group.Comment: 17 pages, 8+A1 figures. Accepted for publication on Astronomische Nachrichten on 10th January 2024 available https://onlinelibrary.wiley.com/doi/10.1002/asna.20230158 on-line supplementary material and animations https://web.oapd.inaf.it/bedin/files/PAPERs_eMATERIALs/Luh16AB_II

Targeting hif-1&#945; regulatory pathways as a strategy to hamper tumor-microenvironment interactions in cll

The hypoxia-inducible factor 1 (HIF-1) and the CXCL12/CXCR4 axis regulate the interaction of chronic lymphocytic leukemia cells and the tumor microenvironment. However, the interconnections occurring between HIF-1 and the CXCL12/CXCR4 axis are not fully elucidated. Here, we demonstrate that the CXCL12/CXCR4 axis plays a pivotal role in the positive regulation of the α subunit of HIF-1 (HIF-1α) that occurs in CLL cells co-cultured with stromal cells (SC). Inhibitors acting at different levels on CXCR4 downstream signalling counteract the SC-induced HIF-1α upregulation in CLL cells, also hindering the SC-mediated pro-survival effect. HIF-1α inhibition also exerts off-tumor effects on the SC component, inducing the downregulation of target genes, including CXCL12. Consistently, our data show that pretreatment of leukemic cells and/or SC with idelalisib effectively abrogates the SC-mediated survival support. A combined on-tumor and off-tumor inhibition of HIF-1α was also observed in idelalisib-treated patients, who showed, along with a downregulation of HIF-1α target genes in leukemic cells, a significant decrease in CXCL12 serum concentration and changes in the bone marrow microenvironment. Our data demonstrate that the targeting of HIF-1α or its regulatory pathways acts at the tumor- and SC-level, and may be an appealing strategy to overcome the microenvironment-mediated protection of CLL cells

Party Face Congratulations! Exploring Design Ideas to Help Sighted Users with Emoji Accessibility when Messaging with Screen Reader Users

Emoji are a popular, expressive form of non-verbal communication. However, people often use emoji in ways that result in confusing or cumbersome screen reader output. We created two accessibility support designs: (1) Preview, which displays a basic text transcript of a message with emoji that a screen reader would narrate, and (2) Alert, which summarises potential accessibility issues caused by emoji within a message. We explored our designs using an online survey and provided participants with the option to edit messages that contained emoji, should they choose to do so. We collected 1508 modified messages from 116 sighted participants and conducted a qualitative analysis of the data to identify the strategies participants used when asked to edit a message for accessibility issues and their appreciation of each design. We found that participants preferred the Preview design over Alert since it allows for subjective interpretations of what constitutes an accessible message. We report sighted users' rewriting strategies (e.g., editing the message to move the emoji to the end) and incorrect assumptions about screen readers that would lead to using textual markers that are incompatible with screen readers. We discuss the design implications for future systems for accessible messaging

Targeting hif-1α regulatory pathways as a strategy to hamper tumor-microenvironment interactions in cll

The hypoxia-inducible factor 1 (HIF-1) and the CXCL12/CXCR4 axis regulate the interaction of chronic lymphocytic leukemia cells and the tumor microenvironment. However, the interconnections occurring between HIF-1 and the CXCL12/CXCR4 axis are not fully elucidated. Here, we demonstrate that the CXCL12/CXCR4 axis plays a pivotal role in the positive regulation of the α subunit of HIF-1 (HIF-1α) that occurs in CLL cells co-cultured with stromal cells (SC). Inhibitors acting at different levels on CXCR4 downstream signalling counteract the SC-induced HIF-1α upregulation in CLL cells, also hindering the SC-mediated pro-survival effect. HIF-1α inhibition also exerts off-tumor effects on the SC component, inducing the downregulation of target genes, including CXCL12. Consistently, our data show that pretreatment of leukemic cells and/or SC with idelalisib effectively abrogates the SC-mediated survival support. A combined on-tumor and off-tumor inhibition of HIF-1α was also observed in idelalisib-treated patients, who showed, along with a downregulation of HIF-1α target genes in leukemic cells, a significant decrease in CXCL12 serum concentration and changes in the bone marrow microenvironment. Our data demonstrate that the targeting of HIF-1α or its regulatory pathways acts at the tumor-and SC-level, and may be an appealing strategy to overcome the microenvironment-mediated protection of CLL cells