Pharmacological Polarization of Tumor-Associated Macrophages Toward a CXCL9 Antitumor Phenotype.

Tumor-associated macrophages (TAM) are a diverse population of myeloid cells that are often abundant and immunosuppressive in human cancers. CXCL9 <sup>Hi</sup> TAM has recently been described to have an antitumor phenotype and is linked to immune checkpoint response. Despite the emerging understanding of the unique antitumor TAM phenotype, there is a lack of TAM-specific therapeutics to exploit this new biological understanding. Here, the discovery and characterization of multiple small-molecule enhancers of chemokine ligand 9 (CXCL9) and their targeted delivery in a TAM-avid systemic nanoformulation is reported. With this strategy, it is efficient encapsulation and release of multiple drug loads that can efficiently induce CXCL9 expression in macrophages, both in vitro and in vivo in a mouse tumor model. These observations provide a window into the molecular features that define TAM-specific states, an insight a novel therapeutic anticancer approach is used to discover

Extramedullary Hematopoiesis Generates Ly-6C(high) Monocytes That Infiltrate Atherosclerotic Lesions

BACKGROUND: Atherosclerotic lesions are believed to grow via the recruitment of bone marrow-derived monocytes. Among the known murine monocyte subsets, Ly-6C(high) monocytes are inflammatory, accumulate in lesions preferentially, and differentiate. Here we hypothesized that the bone marrow outsources the production of Ly-6C(high) monocytes during atherosclerosis. METHODS AND RESULTS: Using murine models of atherosclerosis and fate-mapping approaches, we show that hematopoietic stem and progenitor cells (HSPC) progressively relocate from the bone marrow to the splenic red pulp where they encounter GM-CSF and IL-3, clonally expand, and differentiate to Ly-6C(high) monocytes. Monocytes born in such extramedullary niches intravasate, circulate, and accumulate abundantly in atheromata. Upon lesional infiltration, Ly-6C(high) monocytes secrete inflammatory cytokines, reactive oxygen species, and proteases. Eventually, they ingest lipids and become foam cells. CONCLUSIONS: Our findings indicate that extramedullary sites supplement the bone marrow’s hematopoietic function by producing circulating inflammatory cells that infiltrate atherosclerotic lesions

Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy.

The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8 <sup>+</sup> T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in patients with melanoma and correlate with response to anti-PD-1 therapy. Our data demonstrate the functional significance of circadian dynamics in the tumor microenvironment and suggest the importance of leveraging these features for improving future clinical trial design and patient care

Foraminiferal assemblages as palaeoenvironmental bioindicators in Late Jurassic epicontinental platforms: relation with trophic conditions

Foraminiferal assemblages from the neritic environment reveal the palaeoecological impact of nutrient types in relation to shore distance and sedimentary setting. Comparatively proximal siliciclastic settings from the Boreal Domain (Brora section, Eastern Scotland) were dominated by inner−shelf primary production in the water column or in sea bottom, while in relatively seawards mixed carbonate−siliciclastic settings from the Western Tethys (Prebetic, Southern Spain), nutrients mainly derived from the inner−shelf source. In both settings, benthic foraminiferal assemblages increased in diversity and proportion of epifauna from eutrophic to oligotrophic conditions. The proximal setting example (Brora Brick Clay Mb.) corresponds to Callovian offshore shelf deposits with a high primary productivity, bottom accumulation of organic matter, and a reduced sedimentation rate for siliciclastics. Eutrophic conditions favoured some infaunal foraminifera. Lately, inner shelf to shoreface transition areas (Fascally Siltstone Mb.), show higher sedimentation rates and turbidity, reducing euphotic−zone range depths and primary production, and then deposits with a lower organic matter content (high−mesotrophic conditions). This determined less agglutinated infaunal foraminifera content and increasing calcitic and aragonitic epifauna, and calcitic opportunists (i.e., Lenticulina). The comparatively distal setting of the Oxfordian example (Prebetic) corresponds to: (i) outer−shelf areas with lower nutrient input (relative oligotrophy) and organic matter accumulation on comparatively firmer substrates (lumpy lithofacies group) showing dominance of calcitic epifaunal foraminifera, and (ii) mid−shelf areas with a higher sedimentation rate and nutrient influx (low−mesotrophic conditions) favouring potentially deep infaunal foraminifers in comparatively unconsolidated and nutrient−rich substrates controlled by instable redox boundary (marl−limestone rhythmite lithofacies).This research was carried out with the financial support of projects CGL2005−06636−C0201 and CGL2005−01316/BTE, and University of Oslo, Norway−Statoil cooperation. M.R. holds a Juan de la Cierva grant from the Ministry of Science and Technology of Spain

Intergenerational accumulation of impairments in maternal behavior following postnatal social stress

Early adversity such as depressed maternal care can have long-term physiological and behavioral effects on offspring and future generations. Exposure to chronic social stress (CSS), an ethologically model of postpartum depression and anxiety, during lactation impairs maternal care and exerts similar effects on the F1 dam offspring of the stressed F0 dams. These changes associate with increased corticosterone and neuroendocrine alterations. CSS F2 offspring further display decreased social behavior as juveniles and adults and decreased basal levels of corticosterone. This current study investigates the intergenerational inheritance of alterations in maternal behavior in F2 CSS dams together with neuroendocrine and immune markers to explore whether aspects of maternal behavior are intergenerationally inherited through immune and neuroendocrine mechanisms. We find that defects in maternal care behavior persist into the F2 generation with F2 dams exhibiting a pervasively depressed maternal care and increased restlessness throughout lactation. This occurs together with reduced basal cortisol (in contrast to an increase in F1 dams), a lack of changes in neuroendocrine gene expression, and reduced serum ICAM-1 (intercellular adhesion molecule-1) levels - a marker for inflammation and blood–brain barrier integrity. The data support the hypothesis that the effects of chronic social stress can accumulate across multiple generations to depress maternal care, increase restlessness and alter basal functioning of the immune system and hypothalamic pituitary adrenal axis

Versatile neutrophil functions in cancer.

Neutrophils have historically been considered a singular, terminally-differentiated cell population, replete with pre-formed granules, poised to react quickly, aggressively, and somewhat non-specifically in the face of a microbial challenge or tissue injury. However, in recent years, neutrophil biologists have started revisiting this simplistic conception. Many studies have identified complexities in neutrophil biology, and these findings have led the field to redefine neutrophil heterogeneity from multiple angles including their development and maturation, their tissue location, and their ability to respond to various (pathological) stimuli. In this review, we discuss the importance of this reassessment within the context of cancer. Experimental evidence supports that neutrophil behavior is diverse, context-dependent, and manipulable; cutting-edge technologies have enabled the identification of neutrophil heterogeneity with high resolution and in an unbiased manner, revealing what may be critical underpinnings of these diverse behaviors, and enabling sophisticated computational assessments of specific programs and interactions. We are coming ever closer to delineating a holistic picture of neutrophil heterogeneity and how it may interplay with cancer stage, tumor microenvironment, and therapy. All of this together paints a promising picture when considering how clinical practice may harness the heterogeneity of these cells, for biomarkers or therapeutic approaches, leveraging what we are learning about these powerful and plentiful immune effectors

Clinical relevance of tumour-associated macrophages.

In the past decade, substantial advances have been made in understanding the biology of tumour-associated macrophages (TAMs), and their clinical relevance is emerging. A particular aspect that is becoming increasingly clear is that the interaction of TAMs with cancer cells and stromal cells in the tumour microenvironment enables and sustains most of the hallmarks of cancer. Therefore, manipulation of TAMs could enable improved disease control in a substantial fraction of patients across a large number of cancer types. In this Review, we examine the diversity of TAMs in various cancer indications and how this heterogeneity is being revisited with the advent of single-cell technologies, and then explore the current knowledge on the functional roles of different TAM states and the prognostic and predictive value of TAM-related signatures. We also review agents targeting TAMs that are currently being or will soon be tested in clinical trials, and how manipulations of TAMs can improve existing anticancer treatments. Finally, we discuss how TAM-targeting approaches could be further integrated into routine clinical practice, considering a precision oncology approach and viewing TAMs as a dynamic population that can evolve under treatment pressure