Cancer-associated fibroblasts induce antigen-specific deletion of CD8 + T Cells to protect tumour cells.

Tumours have developed strategies to interfere with most steps required for anti-tumour immune responses. Although many populations contribute to anti-tumour responses, tumour-infiltrating cytotoxic T cells dominate, hence, many suppressive strategies act to inhibit these. Tumour-associated T cells are frequently restricted to stromal zones rather than tumour islands, raising the possibility that the tumour microenvironment, where crosstalk between malignant and "normal" stromal cells exists, may be critical for T cell suppression. We provide evidence of direct interactions between stroma and T cells driving suppression, showing that cancer-associated fibroblasts (CAFs) sample, process and cross-present antigen, killing CD8+ T cells in an antigen-specific, antigen-dependent manner via PD-L2 and FASL. Inhibitory ligand expression is observed in CAFs from human tumours, and neutralisation of PD-L2 or FASL reactivates T cell cytotoxic capacity in vitro and in vivo. Thus, CAFs support T cell suppression within the tumour microenvironment by a mechanism dependent on immune checkpoint activation

Metallointercalators: structure of rac-bis(ethylenediamine)(9,10-phenanthrenequinone diimine)rhodium(III) tribromide trihydrate

Bis(ethylenediamine)(phenanthrenequinone diimine)rhodium(III) tribromide trihydrate has a nearly planar phenanthrenequinone diimine ligand and two ordered ethylenediamine ligands, giving a distorted octahedral coordination to the compound. The N-Rh-N angles range from 77.1 (6) to 96.5°, with the largest deviations from 90° associated with the N atoms of the phenanthrenequinone diimine ligand. The two Rh-N distances involving these N atoms are 0.05 Å shorter than Rh-N distances to ethylenediamine ligands; other distances and angles are within normal ranges

Microenvironmental modulation of the developing tumour: an immune-stromal dialogue.

Successful establishment of a tumour relies on a cascade of interactions between cancer cells and stromal cells within an evolving microenvironment. Both immune and nonimmune cellular components are key factors in this process, and the individual players may change their role from tumour elimination to tumour promotion as the microenvironment develops. While the tumour-stroma crosstalk present in an established tumour is well-studied, aspects in the early tumour or premalignant microenvironment have received less attention. This is in part due to the challenges in studying this process in the clinic or in mouse models. Here, we review the key anti- and pro-tumour factors in the early microenvironment and discuss how understanding this process may be exploited in the clinic

Impact of Locally Administered Carboxydextran‐Coated Super‐Paramagnetic Iron Nanoparticles on Cellular Immune Function

Interstitially administered iron oxide particles are currently used for interoperative localization of sentinel lymph nodes (LNs) in cancer staging. Several studies have described concerns regarding the cellular accumulation of iron oxide nanoparticles relating them to phenotype and function deregulation of macrophages, impairing their ability to mount an appropriate immune response once an insult is present. This study aims to address what phenotypic and functional changes occur during lymphatic transit and accumulation of these particles. Data show that 60 nm carboxydextran-coated iron nanoparticles use a noncellular mechanism to reach the draining LNs and that their accumulation in macrophages induces transient phenotypic and functional changes. Nevertheless, macrophages recover their baseline levels of response within 7 days, and are still able to mount an appropriate response to bacterially induced inflammation

Disruption of CD47-SIRPα signaling restores inflammatory function in tumor-associated myeloid-derived suppressor cells

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous immune population with diverse immunosuppressive functions in solid tumors. Here, we explored the role of the tumor microenvironment in regulating MDSC differentiation and immunosuppressive properties via signal-regulatory protein alpha (SIRPα)/CD47 signaling. In a murine melanoma model, we observed progressive increases in monocytic MDSCs and monocyte-derived dendritic cells that exhibited potent T cell-suppressive capabilities. These adaptations could be recapitulated in vitro by exposing hematopoietic stem cells to tumor-derived factors. Engagement of CD47 with SIRPα on myeloid cells reduced their phagocytic capability, enhanced expression of immune checkpoints, increased reactive oxygen species production, and suppressed T cell proliferation. Perturbation of SIRPα signaling restored phagocytosis and antigen presentation by MDSCs, which was accompanied by renewed T cell activity and delayed tumor growth in multiple solid cancers. These data highlight that therapeutically targeting myeloid functions in combination with immune checkpoint inhibitors could enhance anti-tumor immunity

Modelling structural and cellular elements and functional responses to lymphatic-delivered cues in a murine lymph node on a chip

Lymph nodes (LNs) are organs of the immune system, critical for maintenance of homeostasis and initiation of immune responses, yet there are few models that accurately recapitulate LN functions in vitro. To tackle this issue, an engineered murine LN (eLN) has been developed, replicating key cellular components of the mouse LN; incorporating primary murine lymphocytes, fibroblastic reticular cells, and lymphatic endothelial cells. T and B cell compartments are incorporated within the eLN that mimic LN cortex and paracortex architectures. When challenged, the eLN elicits both robust inflammatory responses and antigen-specific immune activation, showing that the system can differentiate between non specific and antigen-specific stimulation and can be monitored in real time. Beyond immune responses, this model also enables interrogation of changes in stromal cells, thus permitting investigations of all LN cellular components in homeostasis and different disease settings, such as cancer. Here, how LN behavior can be influenced by murine melanoma-derived factors is presented. In conclusion, the eLN model presents a promising platform for in vitro study of LN biology that will enhance understanding of stromal and immune responses in the murine LN, and in doing so will enable development of novel therapeutic strategies to improve LN responses in disease

Single-Cell RNA Sequencing Reveals a Dynamic Stromal Niche That Supports Tumor Growth

Here, using single-cell RNA sequencing, we examine the stromal compartment in murine melanoma and draining lymph nodes (LNs) at points across tumor development, providing data at http://www.teichlab.org/data/. Naive lymphocytes from LNs undergo activation and clonal expansion within the tumor, before PD1 and Lag3 expression, while tumor-associated myeloid cells promote the formation of a suppressive niche. We identify three temporally distinct stromal populations displaying unique functional signatures, conserved across mouse and human tumors. Whereas "immune" stromal cells are observed in early tumors, "contractile" cells become more prevalent at later time points. Complement component C3 is specifically expressed in the immune population. Its cleavage product C3a supports the recruitment of C3aR(+) macrophages, and perturbation of C3a and C3aR disrupts immune infiltration, slowing tumor growth. Our results highlight the power of scRNA-seq to identify complex interplays and increase stromal diversity as a tumor develops, revealing that stromal cells acquire the capacity to modulate immune landscapes from early disease.Peer reviewe

Stromal Amyloid β drives Neutrophil extracellular trap formation to augment tumour growth

Tumors are comprised of cancer cells and a network of non-cancerous stromal cells. Cancer-associated fibroblasts (CAFs) are well known to support tumorigenesis and are emerging as immune modulators. While many leukocyte populations are well studied in cancer, neutrophils have received less attention. Neutrophils can release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NETs) in a process termed NETosis. Here, we show that CAFs induce formation of NETs both within the tumor microenvironment and at systemic levels in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on PAD4 and CD11b. Remarkably, CAF-derived Amyloid β was identified as the key factor driving t-NETosis, a protein with significance in both neurodegenerative and inflammatory disorders. Therapeutic inhibition of NETs in established tumors prevented growth, skewing neutrophils to a pro-inflammatory phenotype. Reciprocally, t-NETs enhanced CAF activation phenotypes. Mirroring murine observations, NETs were detected juxtaposed to CAFs in human melanoma and pancreatic adenocarcinoma, and elevated expression of amyloid and β-Secretase correlated with poor prognosis. In summary, we report the existence of cross-talk between CAFs and neutrophils within the tumour microenvironment whereby CAF-induced t-NETosis supports cancer progression, identifying Amyloid β as the protagonist and potential therapeutic target. Significance This study defines the existence of a pro-tumor immunomodulatory function of the stroma showing the induction of Neutrophil Extracellular Traps through CAF-derived Amyloid β. We term this novel process “Tumor-induced NETosis” (t-NETosis) and propose that therapeutic inhibition of this mechanism, which we observe in human melanoma and pancreatic cancer, has the potential to improve patient outcome

Report of the 2016-2017 Student Affairs Standing Committee

The 2016-2017 AACP Student Affairs Standing Committee addressed charges related to recruitment to the profession of pharmacy and a national awareness campaign for pharmacy careers, as well as promotion of student wellness and stress management. The Committee report provides six recommendations to the American Association of Colleges of Pharmacy (AACP) and one proposed policy statement for the AACP House of Delegates related to recruitment to the pharmacy profession. The Committee report also provides three recommendations to AACP and one proposed policy statement for the AACP House of Delegates related to student wellness and stress management. In addition, this report provides recommendations for future AACP Student Affairs Standing Committee work