Tumor-educated Tregs drive organ-specific metastasis in breast cancer by impairing NK cells in the lymph node niche

Breast cancer is accompanied by systemic immunosuppression, which facilitates metastasis formation, but how this shapes organotropism of metastasis is poorly understood. Here, we investigate the impact of mammary tumorigenesis on regulatory T cells (Tregs) in distant organs and how this affects multi-organ metastatic disease. Using a preclinical mouse mammary tumor model that recapitulates human metastatic breast cancer, we observe systemic accumulation of activated, highly immunosuppressive Tregs during primary tumor growth. Tumor-educated Tregs show tissue-specific transcriptional rewiring in response to mammary tumorigenesis. This has functional consequences for organotropism of metastasis, as Treg depletion reduces metastasis to tumor-draining lymph nodes, but not to lungs. Mechanistically, we find that Tregs control natural killer (NK) cell activation in lymph nodes, thereby facilitating lymph node metastasis. In line, an increased Treg/NK cell ratio is observed in sentinel lymph nodes of breast cancer patients compared with healthy controls. This study highlights that immune regulation of metastatic disease is highly organ dependent

Tumor-associated macrophages promote intratumoral conversion of conventional CD4+ T cells into regulatory T cells via PD-1 signalling

While regulatory T cells (Tregs) and macrophages have been recognized as key orchestrators of cancer-associated immunosuppression, their cellular crosstalk within tumors has been poorly characterized. Here, using spontaneous models for breast cancer, we demonstrate that tumor-associated macrophages (TAMs) contribute to the intratumoral accumulation of Tregs by promoting the conversion of conventional CD4+ T cells (Tconvs) into Tregs. Mechanistically, two processes were identified that independently contribute to this process. While TAM-derived TGF-β directly promotes the conversion of CD4+ Tconvs into Tregs in vitro, we additionally show that TAMs enhance PD-1 expression on CD4+ T cells. This indirectly contributes to the intratumoral accumulation of Tregs, as loss of PD-1 on CD4+ Tconvs abrogates intratumoral conversion of adoptively transferred CD4+ Tconvs into Tregs. Combined, this study provides insights into the complex immune cell crosstalk between CD4+ T cells and TAMs in the tumor microenvironment of breast cancer, and further highlights that therapeutic exploitation of macrophages may be an attractive immune intervention to limit the accumulation of Tregs in breast tumors

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Kognitive Prozesse bei der initialen Diagnosefindung und Therapieplanung in der Kieferorthopädie [Cognitive processes in inital diagnosis and treatment planning in orthodontics]

[english] Introduction: The investigation of diagnostic processes in dentistry and particularly in orthodontics is an often neglected subject of research. This study investigates cognitive processes at initial diagnosis and during treatment planning in orthodontics. We differentiated between various levels of experience: dentists without special training, assistants and specialist dentists. The aim was to identify cognitive processes and use this information for the improvement of education. Methods: A case vignette (complete, evaluated diagnostic record of a patient with patient’s history, clinical findings, study model, cephalogram, panoramic x-ray, photographs) was presented to 17 test persons (5 dentists, 5 assistants and 7 specialist dentists). With the help of think-aloud protocols, statements were systematised and quantified to enable statistical analysis. Results: The cognitive process is a complex and variable interaction of different processes. Reduction to a single known cognitive model was not possible. At a high cognitive load, there were no significant differences between groups for processing, but significant differences were found in the order in which the diagnostic records were considered. With increasing experience, less information (15%) was considered. The study model takes up a substantial proportion of diagnosis and treatment planning in terms of time (&gt;30%) and content. Discussion: The initial orthodontic diagnosis and treatment planning is a highly individual process. An integrated model of analytical and non-analytical approaches can be adopted for orthodontics. Target for the improvement of education should be stricter systematics and reduction of the cognitive load. To build individual strategies it may also be helpful to incorporate more case-based exercises. <br>[german] Einführung: Die Untersuchung diagnostischer Prozesse nach kognitiven Gesichtspunkten ist speziell in der Zahnmedizin und Kieferorthopädie bisher wenig betrachtet worden. In dieser Studie werden die kognitiven Prozesse bei der initialen Diagnostik und Therapieplanung in der Kieferorthopädie untersucht. Es wurden verschiedene Erfahrungslevel von Zahnärzten ohne spezielle Ausbildung, Weiterbildungsassistenten und Fachzahnärzten differenziert. Ziel war es, die gedanklichen Prozesse zu erkennen und Konsequenzen für eine Verbesserung der Ausbildung abzuleiten. Methode: Eine Fallvignette (komplette, ausgewertete diagnostische Unterlagen eines Patienten mit Anamnese, klinischem Befund, Studienmodell, Fernröntgenseitbild, Orthopantomogramm, Fotos) wurde 17 Probanden (5 Zahnärzte, 5 Weiterbildungsassistenten und 7 Fachzahnärzte) vorgelegt. Anhand von Think-aloud-Protokollen der Bearbeitung der Fallvignette wurden die Aussagen systematisiert und quantifiziert und damit einer statistischen Betrachtung zugänglich gemacht. Ergebnis: Der kognitive Prozess ist ein komplexes und variables Zusammenwirken verschiedener Abläufe. Eine Reduktion auf ein bekanntes kognitives Modell war nicht möglich. Bei einer hohen Cognitive Load zeigten sich in der Zeit für die Bearbeitung keine signifikanten Unterschiede zwischen den Gruppen, wohl aber erhebliche Differenzen in der Reihenfolge der Betrachtung der Befunde. Mit steigender Berufserfahrung werden weniger Informationen (15%) abgerufen. Sowohl zeitlich (&gt;30%) als auch inhaltlich hat das Studienmodell wesentlichen Anteil an der Diagnostik und Therapieplanung. Diskussion: Die initiale kieferorthopädische Diagnostik und Therapieplanung ist ein hochindividueller Prozess. Es kann ein integriertes Modell aus analytischem und nichtanalytischem Vorgehen für die Kieferorthopädie angenommen werden. Verbesserungen in der Wissensvermittlung sollten eine strengere Systematisierung und Reduktion der kognitiven Belastung zum Ziel haben. Zum Aufbau individueller Strategien könnte auch der vermehrte Einsatz fallbasierter Übungen beitragen

Neoadjuvant immune checkpoint blockade triggers persistent and systemic Treg activation which blunts therapeutic efficacy against metastatic spread of breast tumors

ABSTRACTThe clinical successes of immune checkpoint blockade (ICB) in advanced cancer patients have recently spurred the clinical implementation of ICB in the neoadjuvant and perioperative setting. However, how neoadjuvant ICB therapy affects the systemic immune landscape and metastatic spread remains to be established. Tumors promote both local and systemic expansion of regulatory T cells (Tregs), which are key orchestrators of tumor-induced immunosuppression, contributing to immune evasion, tumor progression and metastasis. Tregs express inhibitory immune checkpoint molecules and thus may be unintended targets for ICB therapy counteracting its efficacy. Using ICB-refractory models of spontaneous primary and metastatic breast cancer that recapitulate the poor ICB response of breast cancer patients, we observed that combined anti-PD-1 and anti-CTLA-4 therapy inadvertently promotes proliferation and activation of Tregs in the tumor, tumor-draining lymph node and circulation. Also in breast cancer patients, Treg levels were elevated upon ICB. Depletion of Tregs during neoadjuvant ICB in tumor-bearing mice not only reshaped the intratumoral immune landscape into a state favorable for ICB response but also induced profound and persistent alterations in systemic immunity, characterized by elevated CD8+ T cells and NK cells and durable T cell activation that was maintained after treatment cessation. While depletion of Tregs in combination with neoadjuvant ICB did not inhibit primary tumor growth, it prolonged metastasis-related survival driven predominantly by CD8+ T cells. This study demonstrates that neoadjuvant ICB therapy of breast cancer can be empowered by simultaneous targeting of Tregs, extending metastasis-related survival, independent of a primary tumor response

Tumor-educated Tregs drive organ-specific metastasis in breast cancer by impairing NK cells in the lymph node niche

Breast cancer is accompanied by systemic immunosuppression, which facilitates metastasis formation, but how this shapes organotropism of metastasis is poorly understood. Here, we investigate the impact of mammary tumorigenesis on regulatory T cells (Tregs) in distant organs and how this affects multi-organ metastatic disease. Using a preclinical mouse mammary tumor model that recapitulates human metastatic breast cancer, we observe systemic accumulation of activated, highly immunosuppressive Tregs during primary tumor growth. Tumor-educated Tregs show tissue-specific transcriptional rewiring in response to mammary tumorigenesis. This has functional consequences for organotropism of metastasis, as Treg depletion reduces metastasis to tumor-draining lymph nodes, but not to lungs. Mechanistically, we find that Tregs control natural killer (NK) cell activation in lymph nodes, thereby facilitating lymph node metastasis. In line, an increased Treg/NK cell ratio is observed in sentinel lymph nodes of breast cancer patients compared with healthy controls. This study highlights that immune regulation of metastatic disease is highly organ dependent

IL-5-producing CD4+ T cells and eosinophils cooperate to enhance response to immune checkpoint blockade in breast cancer

Immune checkpoint blockade (ICB) has heralded a new era in cancer therapy. Research into the mechanisms underlying response to ICB has predominantly focused on T cells; however, effective immune responses require tightly regulated crosstalk between innate and adaptive immune cells. Here, we combine unbiased analysis of blood and tumors from metastatic breast cancer patients treated with ICB with mechanistic studies in mouse models of breast cancer. We observe an increase in systemic and intratumoral eosinophils in patients and mice responding to ICB treatment. Mechanistically, ICB increased IL-5 production by CD4(+) T cells, stimulating elevated eosinophil production from the bone marrow, leading to systemic eosinophil expansion. Additional induction of IL-33 by ICB-cisplatin combination or recombinant IL-33 promotes intratumoral eosinophil infiltration and eosinophil-dependent CD8(+) T cell activation to enhance ICB response. This work demonstrates the critical role of eosinophils in ICB response and provides proof-of-principle for eosinophil engagement to enhance ICB efficacy.Pathogenesis and treatment of chronic pulmonary disease