Amphiregulin couples IL1RL1+ regulatory T cells and cancer-associated fibroblasts to impede antitumor immunity.

Regulatory T (Treg) cells and cancer-associated fibroblasts (CAFs) jointly promote tumor immune tolerance and tumorigenesis. The molecular apparatus that drives Treg cell and CAF coordination in the tumor microenvironment (TME) remains elusive. Interleukin 33 (IL-33) has been shown to enhance fibrosis and IL1RL1+ Treg cell accumulation during tumorigenesis and tissue repair. We demonstrated that IL1RL1 signaling in Treg cells greatly dampened the antitumor activity of both IL-33 and PD-1 blockade. Whole tumor single-cell RNA sequencing (scRNA-seq) analysis and blockade experiments revealed that the amphiregulin (AREG)-epidermal growth factor receptor (EGFR) axis mediated cross-talk between IL1RL1+ Treg cells and CAFs. We further demonstrated that the AREG/EGFR axis enables Treg cells to promote a profibrotic and immunosuppressive functional state of CAFs. Moreover, AREG mAbs and IL-33 concertedly inhibited tumor growth. Our study reveals a previously unidentified AREG/EGFR-mediated Treg/CAF coupling that controls the bifurcation of fibroblast functional states and is a critical barrier for cancer immunotherapy.

Synergism Between IL21 and Anti-PD-1 Combination Therapy is Underpinned by the Coordinated Reprogramming of the Immune Cellular Network in the Tumor Microenvironment.

T cell-stimulating cytokines and immune checkpoint inhibitors (ICI) are an ideal combination for increasing response rates of cancer immunotherapy. However, the results of clinical trials have not been satisfying. It is important to understand the mechanism of synergy between these two therapeutic modalities. Here, through integrated analysis of multiple single-cell RNA sequencing (scRNA-seq) datasets of human tumor-infiltrating immune cells, we demonstrate that IL21 is produced by tumor-associated T follicular helper cells and hyperactivated/exhausted CXCL13+CD4+ T cells in the human tumor microenvironment (TME). In the mouse model, the hyperactivated/exhausted CD4+ T cell-derived IL21 enhances the helper function of CD4+ T cells that boost CD8+ T cell-mediated immune responses during PD-1 blockade immunotherapy. In addition, we demonstrated that IL21's antitumor activity did not require T-cell trafficking. Using scRNA-seq analysis of the whole tumor-infiltrating immune cells, we demonstrated that IL21 treatment in combination with anti-PD-1 blockade synergistically drives tumor antigen-specific CD8+ T cells to undergo clonal expansion and differentiate toward the hyperactive/exhausted functional state in the TME. In addition, IL21 treatment and anti-PD-1 blockade synergistically promote dendritic cell (DC) activation and maturation to mature DC as well as monocyte to type 1 macrophage (M1) differentiation in the TME. Furthermore, the combined treatment reprograms the immune cellular network by reshaping cell-cell communication in the TME. Our study establishes unique mechanisms of synergy between IL21 and PD-1-based ICI in the TME through the coordinated promotion of type 1 immune responses. Significance: This study reveals how cytokine and checkpoint inhibitor therapy can be combined to increase the efficacy of cancer immunotherapy.

Daytime Sleepiness in Children With Asthma: Examining Respiratory and Non-respiratory Factors.

Objective Daytime sleepiness is common in youth with asthma (YWA). Treatments designed to mitigate daytime sleepiness in YWA require an understanding of the primary causes of this problem. We examined respiratory- and non-respiratory-related factors associated with daytime sleepiness in YWA. Methods One hundred YWA (eight to 17 years old) were included in a cross-sectional study. Daytime sleepiness, quality of life, anxiety, bedtime cellphone use, and respiratory symptoms were self-reported. Asthma severity, lung function, and the number of prescribed medications were obtained from electronic medical records. Multivariable regression models identifying variables associated with daytime sleepiness were generated. Results Participants were 54% male and 45% Black, with a mean age of 12.1 years. The multivariable regression model showed decreased quality of life (b = -0.328, p = 0.004) and increased bedtime cellphone use (b = 0.300, p = 0.004)were significantly related to daytime sleepiness, while anxiety (b = 0.213, p = 0.05), prescribed asthma medications (b = 0.173, p = 0.05), and worse lung function (b = -0.173, p = 0.05)were marginally related to daytime sleepiness. Conclusions In addition to optimizing asthma control, strategies targeting anxiety, quality of life, and nocturnal cellphone use are important to mitigate daytime sleepiness in YWA.

Computed Three-Dimensional Atomic Force Microscopy Images of Biopolymers Using the Jarzynski Equality.

Three-dimensional atomic force microscopy (3D-AFM) has resolved three-dimensional distributions of solvent molecules at solid-liquid interfaces at the subnanometer scale. This method is now being extended to the imaging of biopolymer assemblies such as chromosomes or proteins in cells, with the expectation of being able to resolve their three-dimensional structures. Here, we have developed a computational method to simulate 3D-AFM images of biopolymers by using the Jarzynski equality. It is found that some parts of the fiber structure of biopolymers are indeed resolved in the 3D-AFM image. The dependency of 3D-AFM images on the vertical scanning velocity is investigated, and optimum scanning velocities are found. It is also clarified that forces in nonequilibrium processes are measured in 3D-AFM measurements when the dynamics of polymers are slower than the scanning of the probe.

The IL-1 family in tumorigenesis and antitumor immunity.

The IL-1 family of cytokines consists of IL-1α, IL-1ß, IL-18, IL-33, IL-36α, IL-36ß, and IL-36γ. These proteins form four signaling receptor complexes: the IL-1 receptor (IL-1R1 and IL-1RAcP), the IL-18 receptor (IL-18Rα and IL-18Rß), the IL-33 receptor (ST2 and IL-1RAcP), and the IL-36 receptor (IL-1Rrp2 and IL-1RAcP). The formation of receptor complexes is also regulated by various antagonistic molecules and decoy receptors. The IL-1 family cytokines are induced and secreted by both innate immune cells and tissue cells upon infection and tissue damage. Thus, they play a diverse role in mediating both innate and adaptive immune responses. During tumor development and cancer treatment, the expression of the IL-1 gene family is differentially regulated in tumor cells, tissue stromal cells, and immune cells in a stage specific and tissue specific manner. Like other cytokines, the IL-1 family proteins have pleiotropic functions that are dependent on diverse arrays of target cells. As a result, they play a complex role in tumorigenesis, cancer metastasis, immune suppression, and cancer immune surveillance. Here, we focus on reviewing experimental evidence demonstrating how members of the IL-1 family influence cancer development at the cellular and molecular level. The unique mechanisms of this group of cytokines make them attractive targets for new cancer therapy.

Turning walking pneumonia into recurrent abscesses: a curious case of CVID and review of the literature.

BACKGROUND: Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder associated with a broad symptom presentation that is still being characterized. We report a rare case of recurrent mycoplasma skin abscesses in a patient with a history of autoimmune disorders and prolonged mycoplasma pneumonia who was diagnosed with CVID. CASE PRESENTATION: A 34-year-old woman presented with a history of recurrent abscesses previously confirmed positive for Mycoplasma pneumoniae. Her past medical history of recurrent mycoplasma abscesses, prolonged mycoplasma pneumonia, and autoimmune disorders (mixed connective tissue disease and immune thrombocytopenia) raised suspicion of CVID. Workup included negative anti-mycoplasma antibody titers, hypogammaglobulinemia, and negative anti-pneumococcal antibody titers despite prior vaccination, solidifying the diagnosis of CVID. The patient was discharged on antibiotic and intravenous immunoglobulin therapy and now follows allergy and immunology long-term for treatment. CONCLUSIONS: Her diagnostic history underscores the importance of considering the various criteria of CVID for diagnosis, and her unique presentation of M. pneumoniae skin abscesses highlights the broad sequelae patients with CVID can manifest.

Inequities in coronavirus disease 2019 (COVID-19) Vaccination Rates Among Adolescents in Massachusetts: A Cross-sectional Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has disproportionately affected more socioeconomically disadvantaged persons and areas. We sought to determine how certain sociodemographic factors were correlated to adolescents' COVID-19 vaccination rates in towns and cities ("communities") in the Commonwealth of Massachusetts. METHODS: Data on COVID-19 vaccination rates were obtained over a 20-week period from 30 March 2021 to 10 August 2021. Communities' adolescent (ages 12-19) vaccination rates were compared across quintiles of community-level income, COVID-19 case rate, and proportion of non-Hispanic Black or Hispanic individuals. Other variables included population density and earlier COVID-19 vaccination rates of adolescents and adults, averaged from 30 March to 11 May to determine their effects on vaccination rates on 10 August. Linear and logistic regression was used to estimate individual effects of variables on adolescent vaccination rates. RESULTS: Higher median household income, lower proportion of Black or Hispanic individuals, higher early adolescent COVID-19 vaccination rates, and higher early adult COVID-19 vaccination rates were associated with higher later adolescent COVID-19 vaccination rates. Income per $10 000 (adjusted odds ratio [aOR] = 1.01 [95% confidence interval [CI] = 1.01-1.02]), proportion of Hispanic individuals (aOR = 1.33 [95% CI: 1.13-1.56]), early adolescent COVID-19 vaccination rates (aOR = 5.28 [95% CI: 4.67-5.96]), and early adult COVID-19 vaccination rates (aOR = 2.31 [95% CI: 2.02-2.64]) were associated with higher adolescent COVID-19 vaccination on 10 August, whereas proportion of Black individuals approached significance (aOR = 1.26 [95% CI: .98-1.61]). CONCLUSIONS: Vaccination efforts for adolescents in Massachusetts should focus on boosting vaccination rates early in communities with the lowest incomes and greatest proportion of Hispanic individuals and consider targeting communities with a greater proportion of Black individuals.

The Half-Life-Extended IL21 can Be Combined With Multiple Checkpoint Inhibitors for Tumor Immunotherapy.

In the era of immune checkpoint blockade cancer therapy, cytokines have become an attractive immune therapeutics to increase response rates. Interleukin 21 (IL21) as a single agent has been evaluated for cancer treatment with good clinical efficacy. However, the clinical application of IL21 is limited by a short half-life and concern about potential immune suppressive effect on dendritic cells. Here, we examined the antitumor function of a half-life extended IL21 alone and in combination with PD-1 blockade using preclinical mouse tumor models. We also determined the immune mechanisms of combination therapy. We found that combination therapy additively inhibited the growth of mouse tumors by increasing the effector function of type 1 lymphocytes. Combination therapy also increased the fraction of type 1 dendritic cells (DC1s) and M1 macrophages in the tumor microenvironment (TME). However, combination therapy also induced immune regulatory mechanisms, including the checkpoint molecules Tim-3, Lag-3, and CD39, as well as myeloid derived suppressor cells (MDSC). This study reveals the mechanisms of IL21/PD-1 cooperation and shed light on rational design of novel combination cancer immunotherapy.