Emerging Innate Immune Cells in Cancer Immunotherapy: Promises and Challenges.

Immune checkpoint inhibitor (ICI)-based therapy has made an unprecedented impact on survival benefit for a subset of cancer patients; however, only a subset of cancer patients is benefiting from ICI therapy if all cancer types are considered. With the advanced understanding of interactions of immune effector cell types and tumors, cell-based therapies are emerging as alternatives to patients who could not benefit from ICI therapy. Pioneering work of chimeric antigen receptor T (CAR-T) therapy for hematological malignancies has brought encouragement to a broad range of development for cellular-based cancer immunotherapy, both innate immune cell-based therapies and T-cell-based therapies. Innate immune cells are important cell types due to their rapid response, versatile function, superior safety profiles being demonstrated in early clinical development, and being able to utilize multiple allogeneic cell sources. Efforts on engineering innate immune cells and exploring their therapeutic potential are rapidly emerging. Some of the therapies, such as CD19 CAR natural killer (CAR-NK) cell-based therapy, have demonstrated comparable early efficacy with CD19 CAR-T cells. These studies underscore the significance of developing innate immune cells for cancer therapy. In this review, we focus on the current development of emerging NK cells, γδ T cells, and macrophages. We also present our views on potential challenges and perspectives to overcome these challenges.

Politics and health care spending in the United States: A case study from the passage of the 2003 Medicare Modernization Act.

This paper analyzes the interplay between congressional politics, the actions of the executive branch, and hospitals' regulated Medicare payments. We focus on the 2003 Medicare Modernization Act (MMA) and analyze a provision in the law - Section 508 - that raised certain hospitals' regulated payments. We show, via our analysis of the Section 508 program, that Medicare payments are malleable and can be influenced by political dynamics. In the cross-section, hospitals represented by members of Congress who voted "yea" on the MMA were more likely to receive Section 508 payment increases. We interviewed the Secretary of Health and Human Services who oversaw the MMA, and he described how these payment increases were designed to win support for the law. The Section 508 payment increases raised hospitals' activity and spending. Members of Congress representing recipient hospitals received increased campaign contributions after the Section 508 payment increases were extended. Ultimately, our analysis highlights how Medicare payment increases can serve as an appealing tool for legislative leaders working to win votes for wider pieces of legislation.

Language Disparities in Caregiver Satisfaction with Physician Communication at Well Visits from 0-2 Years.

OBJECTIVE: This study aimed to describe caregiver satisfaction with physician communication over the first two years of life and examine differences by preferred language and the relationship to physician continuity. METHODS: Longitudinal data were collected at well visits (2 months to 2 years) from participants in a randomized controlled trial to prevent childhood obesity. Satisfaction with communication was assessed using the validated Communication Assessment Tool (CAT) questionnaire. Changes in the odds of optimal scores were estimated in mixed-effects logistic regression models to evaluate the associations between satisfaction over time and language, interpreter use, and physician continuity. RESULTS: Of 865 caregivers, 35% were Spanish-speaking. Spanish-speaking caregivers without interpreters had lower odds of an optimal satisfaction score compared with English speakers during the first 2 years, beginning at 2 months [OR 0.64 (95% CI: 0.43, 0.95)]. There was no significant difference in satisfaction between English-speaking caregivers and Spanish-speaking caregivers with an interpreter. The odds of optimal satisfaction scores increased over time for both language groups. For both language groups, odds of an optimal satisfaction score decreased each time a new physician was seen for a visit [OR 0.82 (95% CI: 0.69, 0.97)]. CONCLUSION: Caregiver satisfaction with physician communication improves over the first two years of well-child visits for both English- and Spanish-speakers. A loss of physician continuity over time was also associated with lower satisfaction. Future interventions to ameliorate communication disparities should ensure adequate interpreter use for primarily Spanish-speaking patients and address continuity issues to improve communication satisfaction.

CD8+ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4.

Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors, contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4-dependent (GPX4-dependent) ferroptosis. Here, we show the necessity of adenosine A2A receptor (A2AR) signaling and the GSH/GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8+ T cells. Activated CD8+ T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy. Additionally, we identify a particular cluster of intratumoral CD8+ T cells expressing a putative gene signature of GSH metabolism (GMGS) in association with clinical response and survival across several human cancers. Our study addresses a key role of GSH/GPX4 and adenosinergic pathways in fine-tuning the metabolic fitness of antitumor CD8+ T cells.

Reactive axillary lymph nodes after COVID-19 mRNA vaccination: comparison of mRNA vs. attenuated whole-virus vaccines.

OBJECTIVE: To compare the incidence and natural course of reactive axillary lymph nodes (RAL) between mRNA and attenuated whole-virus vaccines using Deauville criteria. METHODS: In this multi-institutional PET-CT study comprising multiple vaccine types (Pfizer-BioNTech/Comirnaty, Moderna/Spikevax, Sinovac/CoronaVac and Janssen vaccines), we evaluated the incidence and natural course of RAL in a large cohort of oncological patients utilizing a standardized Deauville scaling system (n=522; 293 Female, Deauville 3-5 positive for RAL). Univariate and multivariate analyses were conducted to evaluate the predictive value of clinical parameters (absolute neutrophil count [ANC], platelets, age, sex, tumor type, and vaccine-to-PET interval) for PET positivity. RESULTS: Pfizer-BioNTech/Comirnaty and Moderna vaccines revealed similar RAL incidences for the first 20 days after the second dose of vaccine administration (44% for the first 10 days for both groups, 26% vs. 20% for 10-20 days, respectively for Moderna and Pfizer). However, Moderna recipients revealed significantly higher incidences of RAL after 20 days compared to Pfizer-BioNTech/Comirnaty, with nodal reactivity spanning up to the 9th week post-vaccination (15% vs. 4%, respectively P  < 0.001). No RAL was observed in patients who received either a single dose of J&J vaccine or two doses of CroronaVac. Younger patients showed increased likelihood of RAL, otherwise, clinical/demographic parameters were not predictive of RAL ( P  = 0.014 for age, P  > 0.05 for additional clinical/demographic parameters). CONCLUSION: RAL based on strict PET criteria was observed with mRNA but not with attenuated whole-virus vaccines, in line with higher immunogenicity and stronger protection offered by mRNA vaccines.

The Human Soluble NKG2D Ligand Differentially Impacts Tumorigenicity and Progression in Temporal and Model-Dependent Modes.

NKG2D is an activating receptor expressed by all human NK cells and CD8 T cells. Harnessing the NKG2D/NKG2D ligand axis has emerged as a viable avenue for cancer immunotherapy. However, there is a long-standing controversy over whether soluble NKG2D ligands are immunosuppressive or immunostimulatory, originating from conflicting data generated from different scopes of pre-clinical investigations. Using multiple pre-clinical tumor models, we demonstrated that the impact of the most characterized human solid tumor-associated soluble NKG2D ligand, the soluble MHC I chain-related molecule (sMIC), on tumorigenesis depended on the tumor model being studied and whether the tumor cells possessed stemness-like properties. We demonstrated that the potential of tumor formation or establishment depended upon tumor cell stem-like properties irrespective of tumor cells secreting the soluble NKG2D ligand sMIC. Specifically, tumor formation was delayed or failed if sMIC-expressing tumor cells expressed low stem-cell markers; tumor formation was rapid if sMIC-expressing tumor cells expressed high stem-like cell markers. However, once tumors were formed, overexpression of sMIC unequivocally suppressed tumoral NK and CD8 T cell immunity and facilitated tumor growth. Our study distinguished the differential impacts of soluble NKG2D ligands in tumor formation and tumor progression, cleared the outstanding controversy over soluble NKG2D ligands in modulating tumor immunity, and re-enforced the viability of targeting soluble NKG2D ligands for cancer immunotherapy for established tumors.

Clearing soluble MIC reverses the impaired function of natural killer cells from patients with multiple myeloma.

BACKGROUND: Major histocompatibility complex (MHC) class I chain-related protein (MIC) is a stress-induced ligand released from multiple myeloma (MM) cells during progression, and soluble MIC impairs natural killer group 2D (NKG2D) activating receptor-mediated recognition and function of natural killer (NK) cells. However, whether clearing soluble MIC with a monoclonal antibody (mAb) can restore NK cell activity of MM patients remains undetermined. METHODS: We analyzed The Cancer Genome Atlas (TCGA) Multiple Myeloma Research Foundation (MMRF) CoMMpass data set to examine the prognostic significance of MIC expression in MM. We examined the level of soluble MIC in paired peripheral blood (PB) and bone marrow (BM) plasma of patients with MM at diagnosis by ELISA. We evaluated the correlation between the level of soluble MIC and immunophenotype of NK cells from MM patients by multicolor flow cytometry. We also generated MIC-overexpressing MM cell line and characterized the cytotoxic function of patient NK cells in the presence of soluble MIC, and examined the impact of clearing soluble MIC with a humanized mAb (huB10G5). RESULTS: We characterize the importance of MICA in MM by revealing the significantly better overall survival of patients with high MICA expression from TCGA MMRF CoMMpass data set. The level of soluble MICA is more highly elevated in MM than in precursor stages, and the concentration of soluble MICA is higher in BM plasma than in PB. The concentration of soluble MICA in BM was correlated with myeloma burden, while it was negatively correlated with the frequency of NKG2D+ NK cells in diagnostic BM aspirates of MM patients. Soluble MICA downregulated NKG2D expression and decreased cytotoxicity of MM patient NK cells ex vivo, which were reversed by a humanized soluble MIC-clearing mAb (huB10G5) with enhanced degranulation of NK cells. CONCLUSIONS: Our findings indicate targeting soluble MIC with huB10G5 might be a viable therapeutic approach to promote NKG2D-dependent cellular immunotherapy outcome in MM.

SMR peptide antagonizes Staphylococcus aureus biofilm formation.

The emergence and international dissemination of multi-drug resistant Staphylococcus aureus (S. aureus) strains challenge current antibiotic-based therapies, representing an urgent threat to public health worldwide. In the U.S. alone, S. aureus infections are responsible for 11,000 deaths and 500,000 hospitalizations annually. Biofilm formation is a major contributor to antibiotic tolerance and resistance-induced delays in empirical therapy with increased infection severity, frequency, treatment failure, and mortality. Developing novel treatment strategies to prevent and disrupt biofilm formation is imperative. In this article, we test the Secretion Modification Region (SMR) peptides for inhibitory effects on resistant S. aureus biofilm-forming capacity by targeting the molecular chaperone DnaK. The dose effect of SMR peptides on biofilm formation was assessed using microtiter plate methods and confocal microscopy. Interaction between the antagonist and DnaK was determined by immune precipitation with anti-Flag M2 Affinity and Western blot analysis. Increasing SMR peptide concentrations exhibited increasing blockade of S. aureus biofilm formation with significant inhibition found at 18 µM, 36 µM, and 72 µM. This work supports the potential therapeutic benefit of SMR peptides in reducing biofilm viability and could improve the susceptibility to antimicrobial agents.IMPORTANCEThe development of anti-biofilm agents is critical to restoring bacterial sensitivity, directly combating the evolution of resistance, and overall reducing the clinical burden related to pervasive biofilm-mediated infections. Thus, in this study, the SMR peptide, a novel small molecule derived from the HIV Nef protein, was preliminarily explored for anti-biofilm properties. The SMR peptide was shown to effectively target the molecular chaperone DnaK and inhibit biofilm formation in a dose-dependent manner. These results support further investigation into the mechanism of SMR peptide-mediated biofilm formation and inhibition to benefit rational drug design and the identification of therapeutic targets.

Patient Removal of Urinary Catheters After Urogynecologic Surgery: A Randomized Controlled Trial.

OBJECTIVE: To compare postoperative urinary retention rates in the early postoperative period between home and office catheter removal. Secondary outcomes included pain, difficulty, satisfaction, likelihood to use again, and health care utilization. METHODS: We conducted a nonblinded, randomized controlled, noninferiority trial of women undergoing surgery for stress incontinence and prolapse from March 2021 to June 2022. Exclusion criteria were preoperative voiding dysfunction (need for self-catheterization or postvoid residual [PVR] greater than 150 mL), urethral bulking, and need for prolonged postoperative catheterization. Participants discharged with indwelling catheters because of an initial failed void trial were randomized 1:1 to home compared with office removal on postoperative day 3-4. For home removal, participants were instructed to remove the catheter at 7 am and to drink two glasses of water. If they had difficulty voiding 5 hours after catheter removal, they came to the office for a void trial. For office removal, participants returned for a backfill void trial with PVR assessment. Our primary outcome was rate of early postoperative urinary retention , defined as confirmed retention (PVR greater than half the voided volume) after catheter removal. Secondary outcomes were assessed at a 2-week call. Health care utilization (telephone calls and office visits) related to catheter issues was also assessed. At 80% power and α=0.05, we needed 100 participants (50/group) to detect a noninferiority margin of 11%. RESULTS: Among 117 participants, the home (n=59) and office (n=58) removal groups were similar in mean age (60 years vs 61 years), mean body mass index (29 vs 30), pelvic organ prolapse quantification system stage 3 or 4, and proportion who underwent hysterectomy or apical suspension. Sling procedures were more common in the office group (45.8% vs 77.6%). For our primary outcome, the rate of early postoperative retention was 11.9% in the home group and 22.4% in the office group ( P =.13). Our predetermined noninferiority margin was greater than the upper bound of our 95% CI; thus, we conclude noninferiority of home removal. For secondary outcomes, the home removal group was more likely to report "no pain" ( P =.02) and "very likely" to use this method again ( P =.004). There were no differences in difficulty or satisfaction between groups. Number of nursing calls was not different ( P =.66); however, number of office visits was higher in the office group (median 0 [interquartile range 0-1] vs 1 [1-1], P <.001). CONCLUSION: Postoperative urinary catheter removal by the patient at home was noninferior to office removal when early urinary retention rates were compared. Participants in the home removal group had fewer office visits and reported low pain, low difficulty, and high satisfaction. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT04783012.

Taiwanese Dermatological Association (TDA) consensus recommendations for the definition, classification, diagnosis, and management of hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory follicular disease characterized by painful, recurrent, inflamed lesions most commonly occurring in the axillary, inguinal, and anogenital regions. HS can inflict immense physical and psychological impact on patients who suffer from this distressing disease. Management of HS generally requires combining various medical and procedural treatment modalities; however, the disease is often recalcitrant to conventional treatments. In light of recent evidence supporting the effectiveness of biologic agents in the treatment of HS, the Taiwanese Dermatological Association established an expert panel of nine dermatologists to develop consensus statements aimed to provide up-to-date evidence-based guidance in optimizing HS patient management in Taiwan. The recommendations described in the statements were summarized in a management algorithm in terms of general care, topical treatment, systemic treatment, and procedural treatment.

Advanced Age in Humans and Mouse Models of Glioblastoma Show Decreased Survival from Extratumoral Influence.

PURPOSE: Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumoral relationships between adult patients with GBM and mice with brain tumors across the lifespan. EXPERIMENTAL DESIGN: Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. In addition, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy. RESULTS: Human patients with GBM ≥65 years of age had a significantly decreased survival compared with their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older patients with GBM, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice. CONCLUSIONS: This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM.

Role of radiotherapy and its contribution to immunotherapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a major contributor to cancer-related deaths, with the incidence of HCC increasing in regions of the world with a high incidence of hepatitis B and C. The therapeutic landscape for HCC management has substantially transformed over recent years, shifting towards a multimodal treatment paradigm. This approach provides a range of medical and surgical interventions aimed at managing the disease effectively. Radiotherapy (RT) has surfaced as a critical player in the preoperative management of inoperable HCC, demonstrating potential in downstaging the disease and achieving disease stability. This advantage may potentially be attributed to the abscopal effect, where localized radiation leads to the regression of metastatic cancer outside of the irradiated site through upregulation of the immune system. The advent of recent technological breakthroughs has paved the way for innovative approaches, notably the integration of immunotherapy and RT. This strategy is emerging as a promising avenue for managing HCC. Preliminary findings from the fusion of RT and immunotherapy are encouraging, with ongoing trials keenly evaluating the optimal parameters for therapy administration, such as timing, dosage, and sequence. The development of combined treatments involving immune checkpoint inhibitors (ICIs) has opened new avenues for advanced HCC treatment. Several immunotherapeutic agents with RT are concurrently being explored for their potential contributions to HCC management.

Clinical characteristics and immune profiles of patients with immune-mediated alopecia associated with COVID-19 vaccinations.

BACKGROUND: The clinical characteristics and pathomechanism for immune-mediated alopecia following COVID-19 vaccinations are not clearly characterized. OBJECTIVE: We investigated the causality and immune mechanism of COVID-19 vaccines-related alopecia areata (AA). STUDY DESIGN: 27 new-onset of AA patients after COVID-19 vaccinations and 106 vaccines-tolerant individuals were enrolled from multiple medical centers for analysis. RESULTS: The antinuclear antibody, total IgE, granulysin, and PARC/CCL18 as well as peripheral eosinophil count were significantly elevated in the patients with COVID-19 vaccines-related AA compared with those in the tolerant individuals (P = 2.03 × 10-5-0.039). In vitro lymphocyte activation test revealed that granulysin, granzyme B, and IFN-γ released from the T cells of COVID-19 vaccines-related AA patients could be significantly increased by COVID-19 vaccine excipients (polyethylene glycol 2000 and polysorbate 80) or spike protein (P = 0.002-0.04). CONCLUSIONS: Spike protein and excipients of COVID-19 vaccines could trigger T cell-mediated cytotoxicity, which contributes to the pathogenesis of immune-mediated alopecia associated with COVID-19 vaccines.

In vitro modeling of CD8+ T cell exhaustion enables CRISPR screening to reveal a role for BHLHE40.

Identifying molecular mechanisms of exhausted CD8 T cells (Tex) is a key goal of improving immunotherapy of cancer and other diseases. However, high-throughput interrogation of in vivo Tex can be costly and inefficient. In vitro models of Tex are easily customizable and quickly generate high cellular yield, enabling CRISPR screening and other high-throughput assays. We established an in vitro model of chronic stimulation and benchmarked key phenotypic, functional, transcriptional, and epigenetic features against bona fide in vivo Tex. We leveraged this model of in vitro chronic stimulation in combination with CRISPR screening to identify transcriptional regulators of T cell exhaustion. This approach identified several transcription factors, including BHLHE40. In vitro and in vivo validation defined a role for BHLHE40 in regulating a key differentiation checkpoint between progenitor and intermediate Tex subsets. By developing and benchmarking an in vitro model of Tex, then applying high-throughput CRISPR screening, we demonstrate the utility of mechanistically annotated in vitro models of Tex.

Compulsive Internet Use Scale for assessment of self-reported problematic internet use in primary school-aged children.

Introduction: The tremendous growth of internet use during past few decades has been primarily led by young people. Despite a plenitude of studies reporting the pros and cons of excessive internet use by adolescents, the internet use of primary school-aged children is under-researched. First, there is lack of reliable and valid cultural invariant self-report instruments for children younger than 11-years-old. Secondly, there is no consensus on whether primary school-aged children can reliably report on their internet use. This study aimed to examine the psychometric properties of the Compulsive Internet Use Scale (CIUS) as reported by primary school-aged children in three different countries/regions. Methods: Paper-pencil format CIUS questionnaires were completed by a total of 691 children aged 8 to 10 years old, 236 of them Latvian, 207 Lithuanian, and 248 Taiwanese, as well as by one of their parents, at two-time points, separated by a one-year interval. The parents also reported on the child's emotional and behavioral difficulties. Methods: Confirmatory factor analysis indicated that for the child self-report, a 10-item CIUS showed the best fit and good psychometric properties: solid structural validity; very good internal consistency; appropriate stability and predictive validity after 1 year; as well as sound sensitivity and specificity when compared to the 14-item CIUS parent-report form. Child self-report CIUS ratings correlated with time online reported by the child and parent and with emotional and behavioral problems reported by the parent. Discussion: This study indicates that children as young as 8-10 years old can reliably and consistently provide valuable information on their problematic use of the internet.

The SWI/SNF chromatin remodeling complexes BAF and PBAF differentially regulate epigenetic transitions in exhausted CD8+ T cells.

CD8+ T cell exhaustion (Tex) limits disease control during chronic viral infections and cancer. Here, we investigated the epigenetic factors mediating major chromatin-remodeling events in Tex-cell development. A protein-domain-focused in vivo CRISPR screen identified distinct functions for two versions of the SWI/SNF chromatin-remodeling complex in Tex-cell differentiation. Depletion of the canonical SWI/SNF form, BAF, impaired initial CD8+ T cell responses in acute and chronic infection. In contrast, disruption of PBAF enhanced Tex-cell proliferation and survival. Mechanistically, PBAF regulated the epigenetic and transcriptional transition from TCF-1+ progenitor Tex cells to more differentiated TCF-1- Tex subsets. Whereas PBAF acted to preserve Tex progenitor biology, BAF was required to generate effector-like Tex cells, suggesting that the balance of these factors coordinates Tex-cell subset differentiation. Targeting PBAF improved tumor control both alone and in combination with anti-PD-L1 immunotherapy. Thus, PBAF may present a therapeutic target in cancer immunotherapy.

PROMIS pain intensity and interference after pelvic organ prolapse surgery.

INTRODUCTION AND HYPOTHESIS: Patient-Reported Outcome Measurement Information System (PROMIS) questionnaires provide valid comparisons across disciplines. Pain measures can be used to track functional outcomes. Limited PROMIS pain data exist in gynecological surgery. We sought to use pain intensity and pain interference short forms to assess pain and recovery after pelvic organ prolapse surgery. METHODS: The PROMIS pain intensity and pain interference questionnaires were given to patients undergoing uterosacral ligament suspension (USLS), sacrospinous ligament fixation (SSLF) or minimally invasive sacrocolpopexy (MISC) at baseline, 1 week, and 6 weeks postoperatively. Clinical minimally important change was defined as a difference of 2-6 T-score points. Mean pain intensity and pain interference T-scores were compared at baseline, 1 week and 6 weeks with ANOVA. Multiple linear regression assessed 1-week scores adjusted for apical suspension type, advanced prolapse, concurrent hysterectomy, concurrent anterior or posterior repair, and concurrent sling. RESULTS: At 1 week, all apical suspension groups showed minimally important change in pain intensity and pain interference T-scores. Between groups at 1 week, pain interference was higher in USLS (66.3±6.6) and MISC (65.5±5.9) than in SSLF (59.2±9.8), p=0.01. Multiple linear regression showed an association of hysterectomy with increases in pain intensity and pain interference. USLS had a higher proportion of concurrent hysterectomy (100%) than SSLF (0%) and MISC (30.8%), p<0.01. No difference was found based on apical suspension type alone. CONCLUSIONS: No differences were found in PROMIS pain intensity and pain at 1 week postoperatively after apical suspension procedures.