9 research outputs found
Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis
Age is a significant risk factor for the development of cancer. However, the mechanisms that drive age-related increases in cancer remain poorly understood. To determine if senescent stromal cells influence tumorigenesis, we develop a mouse model that mimics the aged skin microenvironment. Using this model, here we find that senescent stromal cells are sufficient to drive localized increases in suppressive myeloid cells that contributed to tumour promotion. Further, we find that the stromal-derived senescence-associated secretory phenotype factor interleukin-6 orchestrates both increases in suppressive myeloid cells and their ability to inhibit anti-tumour T-cell responses. Significantly, in aged, cancer-free individuals, we find similar increases in immune cells that also localize near senescent stromal cells. This work provides evidence that the accumulation of senescent stromal cells is sufficient to establish a tumour-permissive, chronic inflammatory microenvironment that can shelter incipient tumour cells, thus allowing them to proliferate and progress unabated by the immune system
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Visualizing Synaptic Transfer of Tumor Antigens among Dendritic Cells
Generation of tumor-infiltrating lymphocytes begins when tumor antigens reach the lymph node (LN) to stimulate T cells, yet we know little of how tumor material is disseminated among the large variety of antigen-presenting dendritic cell (DC) subsets in the LN. Here, we demonstrate that tumor proteins are carried to the LN within discrete vesicles inside DCs and are then transferred among DC subsets. A synapse is formed between interacting DCs and vesicle transfer takes place in the absence of free exosomes. DCs -containing vesicles can uniquely activate T cells, whereas DCs lacking them do not. Understanding this restricted sharing of tumor identity provides substantial room for engineering better anti-tumor immunity
Osteopontin Stimulates Preneoplastic Cellular Proliferation Through Activation of the MAPK Pathway
Stromal-Initiated Changes in the Bone Promote Metastatic Niche Development
More than 85% of advanced breast cancer patients suffer from metastatic bone lesions, yet the mechanisms that facilitate these metastases remain poorly understood. Recent studies suggest that tumor-derived factors initiate changes within the tumor microenvironment to facilitate metastasis. However, whether stromal-initiated changes are sufficient to drive increased metastasis in the bone remains an open question. Thus, we developed a model to induce reactive senescent osteoblasts and found that they increased breast cancer colonization of the bone. Analysis of senescent osteoblasts revealed that they failed to mineralize bone matrix and increased local osteoclastogenesis, the latter process being driven by the senescence-associated secretory phenotype factor, IL-6. Neutralization of IL-6 was sufficient to limit senescence-induced osteoclastogenesis and tumor cell localization to bone, thereby reducing tumor burden. Together, these data suggest that a reactive stromal compartment can condition the niche, in the absence of tumor-derived signals, to facilitate metastatic tumor growth in the bone
Unleashing type-2 dendritic cells to drive protective antitumor CD4+ T cell immunity
Differentiation of proinflammatory CD4+ conventional T cells (Tconv) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4+ Tconv, but then fail to support antitumor CD4+ Tconv differentiation. Regulatory T cell (Treg) depletion enhanced their capacity to elicit strong CD4+ Tconv responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to Treg predicts protective ICOS+ PD-1lo CD4+ Tconv phenotypes and survival. Further, in melanoma patients with low Treg abundance, intratumoral cDC2 density alone correlates with abundant CD4+ Tconv and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4+ Tconv abundance and controls tumor growth
Crowded Field Galaxy Photometry: Precision Colors in the CLASH Clusters
We present a new method for photometering objects in galaxy clusters. We
introduce a mode-filtering technique for removing spatially variable
backgrounds, improving both detection and photometric accuracy (roughly halving
the scatter in the red sequence compared to previous catalogs of the same
clusters). This method is based on robustly determining the distribution of
background pixel values and should provide comparable improvement in
photometric analysis of any crowded fields. We produce new multiwavelength
catalogs for the 25 CLASH cluster fields in all 16 bandpasses from the UV
through the near IR, as well as rest-frame magnitudes. A comparison with
spectroscopic values from the literature finds a ~30% decrease in the redshift
deviation from previously-released CLASH photometry. This improvement in
redshift precision, in combination with a detection scheme designed to maximize
purity, yields a substantial upgrade in cluster member identification over the
previous CLASH galaxy catalog. We construct luminosity functions for each
cluster, reliably reaching depths of at least 4.5 mag below M* in every case,
and deeper still in several clusters. We measure M* , , and their
redshift evolution, assuming the cluster populations are coeval, and find
little to no evolution of , , and M* values consistent with passive evolution. We present a catalog of
galaxy photometry, photometric and spectroscopic redshifts, and rest-frame
photometry for the full fields of view of all 25 CLASH clusters. Not only will
our new photometric catalogs enable new studies of the properties of CLASH
clusters, but mode-filtering techniques, such as those presented here, should
greatly enhance the data quality of future photometric surveys of crowded
fields.Comment: 24 pages, 13 figures. Published in ApJ, 201