ABSTRACT
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.
ABSTRACT
A hallmark of many malignant tumors is dedifferentiated (immature) cells bearing slight or no resemblance to the normal cells from which the cancer originated. Tumor dedifferentiated cells exhibit a higher capacity to survive to chemo and radiotherapies and have the ability to incite tumor relapse. Inducing cancer cell differentiation would abolish their self-renewal and invasive capacity and could be combined with the current standard of care, especially in poorly differentiated and aggressive tumors (with worst prognosis). However, differentiation therapy is still in its early stages and the intrinsic complexity of solid tumor heterogeneity demands innovative approaches in order to be efficiently translated into the clinic. We demonstrate here that microRNA 203, a potent driver of differentiation in pluripotent stem cells (ESCs and iPSCs), promotes the differentiation of mammary gland tumor cells. Combining mouse in vivo approaches and both mouse and human-derived tridimensional organoid cultures, we report that miR-203 influences the self-renewal capacity, plasticity and differentiation potential of breast cancer cells and prevents tumor cell growth in vivo. Our work sheds light on differentiation-based antitumor therapies and offers miR-203 as a promising tool for directly confronting the tumor-maintaining and regeneration capability of cancer cells.
Subject(s)
Breast Neoplasms , MicroRNAs , Humans , Mice , Animals , Female , MicroRNAs/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Neoplasm Recurrence, Local/pathology , Cell Differentiation/genetics , Cell Proliferation/genetics , Neoplastic Stem Cells/pathologyABSTRACT
Las técnicas de devaluación e inflación de la consecuencia se han utilizado para evaluar la asociación respuesta-consecuencia (R-C) en animales. Se realizaron dos experimentos con el objetivo de proponer una técnica que permitiera el estudio de la relación R-C en seres humanos. En el Experimento 1 se encontró que la devaluación de una de las consecuencias en una fase post-condicionamiento reduce selectivamente la respuesta entrenada originalmente con esa consecuencia. En el Experimento 2 la inflación de la consecuencia en una fase post-condicionamiento aumentó selectivamente la respuesta asociada a dicho reforzador. Estos resultados sugieren el desarrollo de una asociación R-C durante el condicionamiento instrumental humano (AU)
