Multiplex spatial analysis reveals increased CD137 expression and m-MDSC neighboring tumor cells in refractory classical Hodgkin Lymphoma.

The Hodgkin and Reed - Sternberg (HRS) cells in classical Hodgkin Lymphoma (cHL) actively modify the immune tumor microenvironment (TME) attracting immunosuppressive cells and expressing inhibitory molecules. A high frequency of myeloid cells in the TME is correlated with an unfavorable prognosis, but more specific and rare cell populations lack precise markers. Myeloid-derived suppressor cells (MDSCs) have been identified in the peripheral blood of cHL patients, where they appear to be correlated with disease aggressiveness. TNFRSF9 (CD137) is a T cell co-stimulator expressed by monocytic and dendritic cells. Its expression has also been described in HRS cells, where it is thought to play a role in reducing antitumor responses. Here, we perform qualitative and quantitative analyses of lymphocytic and MDSC subtypes and determine the CD137 cell distribution in cHL primary tumors using multiplex immunofluorescence and automated multispectral imaging. The results were correlated with patients' clinical features. Cells were stained with specific panels of immune checkpoint markers (PD-1, PD-L1, CD137), tumor-infiltrating T lymphocytes (CD3, PD-1), and monocytic cells/MDSCs (CD68, CD14, CD33, Arg-1, CD11b). This approach allowed us to identify distinct phenotypes and to analyze spatial interactions between immune subpopulations and tumor cells. The results confirm CD137 expression by T, monocytic and HRS cells. In addition, the expression of CD137, T exhausted cells, and monocytic MDSCs (m-MDSCs) in the vicinity of malignant HRS cells were associated with a worse prognosis. Our findings reveal new elements of the TME that mediate immune escape, and confirm CD137 as a candidate target for immunotherapy in cHL.

CD137-expressing immune cells and HRS cells are more abundant and in closer proximity in refractory patients than in responders.Monocytic myeloid-derived suppressor cells (m-MDSCs) are associated with unfavorable outcomes and relapse in cHL, unlike granulocytic MDSCs (g-MDSCs), which are located far from HRS cells in non-responders.The cHL tumor microenvironment promotes immune escape in refractory patients by holistically driving polarization and/or recruitment of several cell types with increased expression of CD137 and PD-L1 checkpoints.

Mapping the Spatial Dynamics of the CD4+ T Cell Spectrum in Classical Hodgkin Lymphoma.

As around 25% to 30% of classical Hodgkin lymphoma (cHL) patients with advanced stages do not respond to standard therapies, the tumor microenvironment of cHL is one avenue that may be explored with the aim of improving risk stratification. CD4+ T cells are thought to be one of the main cell types in the tumor microenvironment. However, few immune signatures have been studied, and many of these lack related spatial data. Thus, our aim is to spatially resolve the CD4+ T cell subtypes that influence cHL outcome, depicting new immune signatures or transcriptional patterns that are in crosstalk with the tumor cells. This study was conducted using the NanoString GeoMx digital spatial profiling technology, based on the selection of distinct functional areas of patients' tissues followed by gene-expression profiling. The goals were to assess the differences in CD4+ T cell populations between tumor-rich and immune-predominant areas defined by different CD30 and PD-L1 expression levels and seek correlations with clinical metadata. Our results depict a complex map of CD4+ T cells with different functions and differentiation states that are enriched at distinct locations, the flux of cytokines and chemokines that could be related to these, and the specific relationships with the clinical outcome.

Circulating tumor DNA for monitoring classic Hodgkin lymphoma patients: Correlation with FDG-PET/CT.

The value of circulating tumor DNA (ctDNA) as a biomarker of disease activity in classic Hodgkin lymphoma (cHL) patients has not yet been well established. By profiling primary tumors and ctDNA, we identified common variants between primary tumors and longitudinal plasma samples in most of the cases, confirming high spatial and temporal heterogeneity. Although ctDNA analyses mirrored HRS cell genetics overall, the prevalence of variants shows that none of them can be used as a single biomarker. Conversely, the estimation of hGE/mL, based on measures of total ctDNA, reflects disease activity and is almost perfectly correlated with standard parameters such as PET/CT that are associated with refractoriness.

Immune and stromal transcriptional patterns that influence the outcome of classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) is characterized by a rich immune microenvironment as the main tumor component. It involves a broad range of cell populations, which are largely unexplored, even though they are known to be essential for growth and survival of Hodgkin and Reed-Sternberg cells. We profiled the gene expression of 25 FFPE cHL samples using NanoString technology and resolved their microenvironment compositions using cell-deconvolution tools, thereby generating patient-specific signatures. The results confirm individual immune fingerprints and recognize multiple clusters enriched in refractory patients, highlighting the relevance of: (1) the composition of immune cells and their functional status, including myeloid cell populations (M1-like, M2-like, plasmacytoid dendritic cells, myeloid-derived suppressor cells, etc.), CD4-positive T cells (exhausted, regulatory, Th17, etc.), cytotoxic CD8 T and natural killer cells; (2) the balance between inflammatory signatures (such as IL6, TNF, IFN-γ/TGF-ß) and MHC-I/MHC-II molecules; and (3) several cells, pathways and genes related to the stroma and extracellular matrix remodeling. A validation model combining relevant immune and stromal signatures identifies patients with unfavorable outcomes, producing the same results in an independent cHL series. Our results reveal the heterogeneity of immune responses among patients, confirm previous findings, and identify new functional phenotypes of prognostic and predictive utility.

Health care professionals under programmes for addictions. Personality characteristics of the patients, barriers to treatment and challenges / Programas de atención a los profesionales de la salud con trastornos por uso de sustancias. Idiosincrasias de los usuarios, barreras de accesibilidad y desafíos.

Physicians have privileged information regarding the importance of leading a healthy and drug-free lifestyle, but in everyday reality, they are subject to extreme stressors (work stress, compassion fatigue, burnout syndrome) that have a profound emotional impact. As a result, it is not uncommon for physicians to present substance use disorders and dependencies. Recently, greater attention has been paid to specific factors that may lead to substance use disorder. Despite these efforts, there is a lack of prevention policies and substance use disorders are excluded in the list of occupational diseases. The idiosyncrasies of the tasks and particularities of the behavior of health care workers create a major challenge for the design of effective and safe programs for the health care professional with addictions and their patients. The objective of this work is to carry out an analytical review of the existing literature related to the implementation of specific treatments for health professionals to address SUD. After a tour of the mental health programs in place for health workers in different regions of the world and local resources, a discussion of current information on mental health disorders, as well as prevention and occupational health policies, is presented. In this population, the challenges that must be faced in our reality to create a specific treatment for this population are summarized.

Los médicos cuentan con información privilegiada respecto a la importancia de llevar una vida saludable y libre de drogas, pero la realidad cotidiana señala que están sujetos a estresores extremos (estrés laboral, desgaste por empatía, síndrome de burnout) que producen un impacto emocional profundo. Por ello, no es infrecuente que los médicos presenten trastornos por uso de sustancias y dependencias. Recientemente se ha prestado mayor atención a factores profesionales de las distintas especialidades médicas que puedan propiciar el trastorno por uso de sustancias, aunque faltan políticas de prevención en grupos de mayor riesgo y la incorporación de estos trastornos al listado de enfermedades profesionales por la medicina laboral. La idiosincrasia de las tareas y particularidades de la conducta de trabajadores de la salud generan un desafío mayor para el diseño de programas efectivos y seguros para el profesional con adicciones y sus propios pacientes. El presente trabajo tiene por objetivo realizar una revisión analítica de la bibliografía existente relacionada a la implementación de tratamientos específicos para profesionales de la salud para el abordaje de los trastornos por uso de sustancias. Luego de un recorrido por los programas de salud mental en marcha para trabajadores de la salud en distintas regiones del mundo y los recursos locales, se presenta una discusión de la información actual sobre trastornos de salud mental, así como las políticas de prevención y salud laboral en esta población, se resumen los desafíos con los cuales se deben afrontar en nuestra realidad para el armado de un tratamiento específico para esta población.