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Surgery for renal cell carcinoma (RCC) with venous tumour thrombus (VTT) extension into the renal vein (RV) and/or inferior vena cava (IVC) has high peri-surgical morbidity/mortality. NAXIVA assessed the response of VTT to axitinib, a potent tyrosine kinase inhibitor.NAXIVA was a single-arm, multi-centre, Phase 2 study. In total, 20 patients with resectable clear cell RCC and VTT received upto 8 weeks of pre-surgical axitinib. The primary endpoint was percentage of evaluable patients with VTT improvement by Mayo level on MRI. Secondary endpoints were percentage change in surgical approach and VTT length, response rate (RECISTv1.1) and surgical morbidity.In all, 35% (7/20) patients with VTT had a reduction in Mayo level with axitinib: 37.5% (6/16) with IVC VTT and 25% (1/4) with RV-only VTT. No patients had an increase in Mayo level. In total, 75% (15/20) of patients had a reduction in VTT length. Overall, 41.2% (7/17) of patients who underwent surgery had less invasive surgery than originally planned. Non-responders exhibited lower baseline microvessel density (CD31), higher Ki67 and exhausted or regulatory T-cell phenotype.NAXIVA provides the first Level II evidence that axitinib downstages VTT in a significant proportion of patients leading to reduction in the extent of surgery.NCT03494816.

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 have key roles in this process. Here, we review the major anti‐ and pro‐tumour factors in the early tumour microenvironment and discuss how understanding this process may be exploited in the clinic., 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.

Summary Still’s disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of function of the purine nucleoside enzyme FAMIN is the sole known cause for monogenic Still’s disease. Here we discovered that a FAMIN-enabled purine metabolon in dendritic cells (DCs) restrains CD4+ and CD8+ T cell priming. DCs with absent FAMIN activity prime for enhanced antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in excessive influenza A virus-specific responses. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ∼6% of mankind is homozygous. FAMIN controls membrane trafficking and restrains antigen presentation in an NADH/NAD+-dependent manner by balancing flux through adenine-guanine nucleotide interconversion cycles. FAMIN additionally converts hypoxanthine into inosine, which DCs release to dampen T cell activation. Compromised FAMIN consequently enhances immunosurveillance of syngeneic tumors. FAMIN is a biochemical checkpoint that protects against excessive antiviral T cell responses, autoimmunity, and autoinflammation., Graphical abstract, Highlights • A FAMIN-enabled purine metabolon in dendritic cells restrains T cell priming • FAMIN prevents cytoplasmic NADH/NAD+ reductive stress that enhances priming • Inosine generated from hypoxanthine by FAMIN inhibits T cell priming • FAMIN ameliorates immunopathology in influenza but dampens tumor surveillance, Saveljeva et al. identify a biochemical mechanism in dendritic cells that restrains T cell priming and prevents immunopathology but dampens tumor surveillance. FAMIN enables a purine nucleotide cycle, which prevents cytoplasmic NADH/NAD+ reductive stress that augments antigen presentation, and it generates inosine, which inhibits T cell activation.

INTRODUCTION AND OBJECTIVE:Venous tumor thrombus (VTT) extension occurs in 4-15% cases of renal cell cancer (RCC). Although surgery is performed with curative intent, mortality is high (5-15%). The...

Tumors consist of cancer cells and a network of non-cancerous stroma. Cancer-associated fibroblasts (CAF) are known to support tumorigenesis, and are emerging as immune modulators. Neutrophils release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NET). Here we show that CAFs induce NET formation within the tumor and systemically in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on CAF-derived Amyloid β, a peptide implicated in both neurodegenerative and inflammatory disorders. Inhibition of NETosis in murine tumors skews neutrophils to an anti-tumor phenotype, preventing tumor growth; reciprocally, t-NETs enhance CAF activation. Mirroring observations in mice, CAFs are detected juxtaposed to NETs in human melanoma and pancreatic adenocarcinoma, and show elevated amyloid and β-Secretase expression which correlates with poor prognosis. In summary, we report that CAFs drive NETosis to support cancer progression, identifying Amyloid β as the protagonist and potential therapeutic target., The tumor microenvironment is composed of many cell types that crosstalk to modulate local immunity. Here the authors show that Amyloid β proteins from cancer-associated fibroblasts (CAF) induce neutrophil extracellular trap (NET) production by neutrophils, while NET feeds back to activate CAF, thereby implicating Amyloid β as a potential therapy target.

Ablation of stromal cells expressing fibroblast activation protein-α (FAP) results in cachexia and anemia, and loss of these cells is seen in transplantable tumor models., Fibroblast activation protein-α (FAP) identifies stromal cells of mesenchymal origin in human cancers and chronic inflammatory lesions. In mouse models of cancer, they have been shown to be immune suppressive, but studies of their occurrence and function in normal tissues have been limited. With a transgenic mouse line permitting the bioluminescent imaging of FAP+ cells, we find that they reside in most tissues of the adult mouse. FAP+ cells from three sites, skeletal muscle, adipose tissue, and pancreas, have highly similar transcriptomes, suggesting a shared lineage. FAP+ cells of skeletal muscle are the major local source of follistatin, and in bone marrow they express Cxcl12 and KitL. Experimental ablation of these cells causes loss of muscle mass and a reduction of B-lymphopoiesis and erythropoiesis, revealing their essential functions in maintaining normal muscle mass and hematopoiesis, respectively. Remarkably, these cells are altered at these sites in transplantable and spontaneous mouse models of cancer-induced cachexia and anemia. Thus, the FAP+ stromal cell may have roles in two adverse consequences of cancer: their acquisition by tumors may cause failure of immunosurveillance, and their alteration in normal tissues contributes to the paraneoplastic syndromes of cachexia and anemia.

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.SignificanceThis 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.

Recent advances in our understanding of the molecular biology of gastric and oesophageal cancers have shown that gastroesophageal adenocarcinoma should be considered as one disease spectrum. Clinical management of these cancers is challenging, with poor outcomes in both early and late disease settings. Certain molecular subsets of gastroesophageal adenocarcinoma demonstrate features that suggest immunotherapy could be an effective treatment. Immunogenetic markers, including mismatch repair deficiency, PD-L1 status and tumour infiltrating lymphocytes influence overall prognosis. They may also determine the response to adjuvant and neoadjuvant conventional chemotherapy. Initial results from immunotherapy trials for gastroesophageal cancer have however been mixed, with poor overall responses in the first- and second-line settings. This review aims to discuss how better understanding of these immune and genetic interactions may lead to better selection of patients for conventional and immune based therapies, and therefore improve patient outcomes. We also discuss the challenges in implementing this new understanding in routine practice, and the current limitations of immune based treatments for gastroesophageal cancer.

Despite their abilities to elicit immune responses, both syngeneic tumors and the half-mismatched placenta grow in the host, unlike a tissue allograft that is aggressively rejected. This is because of local and systemic factors that contribute to the immunologic privilege of tumors and the placenta. Checkpoint blockade immunotherapies subvert this privilege, with spectacularly beneficial outcomes in subsets of patients with certain types of cancer. A challenge for the community of scientists and clinicians is to replicate these successes in pregnant patients with cancer, without harm to the placenta. Here we compare and contrast the immunology of cancers and the placenta, and suggest that immunotherapy for pregnant patients with cancer may be a reasonable option, but that this should be explored systematically.

R. Michael Easton, born in Toronto, has been a geologist with the Ontario Geological Survey since 1982, after studying at the University of Western Ontario (B.Sc. 1972), University of Hawaii, (M.Sc. 1976), and Memorial University of Newfoundland (Ph.D. 1982). He specializes in Proterozoic geology, with an emphasis on chronology, stratigraphy, and mapping. He is the author and coauthor of more than 60 geological maps and 150 papers. He was also the 1996 chair of the North American Commission on Stratigraphic Nomenclature (NACSN).James O. Jones (1935–1999) obtained his B.Sc. degree in geology from Midwestern State University in 1962; his M.Sc. degree from Baylor University in 1964; and his Ph.D. in geology from the University of Iowa in 1971. He first taught at Southern Arkansas University, but spent most of his career, from 1977 onward, at the University of Texas at San Antonio. He retired from the U.S. Army Reserve as a lieutenant colonel in 1995. He was the 1997 chair of the NACSN. Alfred C. Lenz spent most of his career teaching paleontology and stratigraphy at the University of Western Ontario, where he is now an emeritus professor. His primary research interest is the study of graptolites. He was the 1998 NACSN chair. Ismael Ferrusquia-Villafranca, born in Mexico City, obtained his B.Sc. degree in biology from Universidad Mexico in 1964 and his M.Sc. degree in paleontology in 1967 and his Ph.D. in geology in 1970, both from the University of Texas at Austin. He is a senior scientific researcher at the Instituto de Geologia, Universidad Nacional Autonoma de Mexico. He is the author and coauthor of more than 160 publications on the geology and vertebrate paleontology of Mexico. He was the 1999 NACSN chair. Ernest A. Mancini is the regional director of the Eastern Gulf Region of the Petroleum Technology Transfer …

An autochthonous model of pancreatic ductal adenocarcinoma (PDA) permitted the analysis of why immunotherapy is ineffective in this human disease. Despite finding that PDA-bearing mice had cancer cell-specific CD8(+) T cells, the mice, like human patients with PDA, did not respond to two immunological checkpoint antagonists that promote the function of T cells: anti-cytotoxic T-lymphocyte-associated protein 4 (α-CTLA-4) and α-programmed cell death 1 ligand 1 (α-PD-L1). Immune control of PDA growth was achieved, however, by depleting carcinoma-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). The depletion of the FAP(+) stromal cell also uncovered the antitumor effects of α-CTLA-4 and α-PD-L1, indicating that its immune suppressive activity accounts for the failure of these T-cell checkpoint antagonists. Three findings suggested that chemokine (C-X-C motif) ligand 12 (CXCL12) explained the overriding immunosuppression by the FAP(+) cell: T cells were absent from regions of the tumor containing cancer cells, cancer cells were coated with the chemokine, CXCL12, and the FAP(+) CAF was the principal source of CXCL12 in the tumor. Administering AMD3100, a CXCL12 receptor chemokine (C-X-C motif) receptor 4 inhibitor, induced rapid T-cell accumulation among cancer cells and acted synergistically with α-PD-L1 to greatly diminish cancer cells, which were identified by their loss of heterozygosity of Trp53 gene. The residual tumor was composed only of premalignant epithelial cells and inflammatory cells. Thus, a single protein, CXCL12, from a single stromal cell type, the FAP(+) CAF, may direct tumor immune evasion in a model of human PDA.

Local immune suppression may account for the paradox that cancers survive in the face of spontaneous or vaccine-induced immune responses. We have previously demonstrated that a stromal cell marked by fibroblast activation protein alpha (FAP) mediates immune suppression in established transplanted tumor models (Kraman et al. Science 2010). This stromal cell is present in 90% of human adenocarcinomas, including pancreatic ductal adenocarcinoma (PDAC). Transplanted models do not always reflect human cancer, so we investigated FAP+ cells in a spontaneous model of PDAC. The KPC mouse uses the Cre recombinase system to target expression of mutations common in human pancreatic cancer (KrasG12D and p53R172H) to pancreatic ductal cells. The mouse develops a spectrum of lesions, from pancreatic intraepithelial neoplasia (PanIN) to PDAC. FAP+ cells are present in PanIN and PDAC. We have previously generated a BAC transgenic mouse that expresses the primate diphtheria toxin receptor under the regulatory elements of the fap gene (FAP-DTR mouse). This allows depletion of FAP+ cells in vivo by administration of diphtheria toxin (DTX). The KPC mouse was crossed with the FAP-DTR mouse to study the effects of FAP+ cell depletion. Tumor growth is arrested during one week of FAP+ cell depletion (mean growth 27.7% treated vs. 85.1% vehicle, p=0.0001). After 72 hours depletion, the percentage of neutrophils in the tumor doubles as measured by flow cytometry (27.8% treated vs. 14.3% vehicle, p=0.0367). This influx is also evident by immunofluorescence microscopy (p=0.0056). There is also a threefold increase in tumor necrosis factor-α mRNA (p=0.0446). These features are suggestive of tissue necrosis. CD8α+ T cells purified from the spleens of tumor-bearing or wild-type mice were incubated with tumor cells in interferon-γ secretion ELISpot assays. T cells purified from tumor-bearing, but not wild-type mice, reacted with the tumor cells indicating a spontaneous antitumor response. Additionally, T cells prepared from one tumor bearing mouse also react with the tumor of another mouse, suggesting that tumor antigens may be shared between KPC tumors. To investigate whether control following FAP+ cell depletion is dependent on this immune response, we administered depleting monoclonal antibodies to CD4 and CD8α concurrently with DTX. Depletion of FAP+ cells has no effect following T cell depletion (mean growth 72.4% treated vs. 80.8% vehicle, p=0.60), indicating that tumor control is immune dependent. In summary, depletion of FAP+ stromal cells results in immune-dependent control of murine PDAC. This control is rapid, suggesting that the preexisting immune response detected by ELISpot assay is effective: T cell exhaustion or selection of nonimmunogenic clones (“cancer immunoediting”) do not account for escape of this tumor from immunosurveillance. Rather, the immune suppressive microenvironment, dependent on the FAP+ cell, masks the tumor from the immune system. If this were the case in humans, a cancer vaccine might not be needed. A therapy that neutralizes immune suppression mediated by FAP+ cells might allow an existing or vaccine induced antitumor response to control tumor growth. Citation Format: James O. Jones, Christine Feig, Edward W. Roberts, Richard J.B. Wells, David A. Tuveson, Douglas T. Fearon. Fibroblast activation protein alpha-expressing stromal cells mediate immune suppression in the KPC mouse model of pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B94.

Tumor Vaccination Success Vaccination with tumor-specific antigens is one of several attempted therapies seeking to harness the immune system, but—unfortunately—this strategy has been unsuccessful, possibly because of the immunosuppressive properties of the tumor microenvironment. Kraman et al. (p. 827 ; see the Perspective by Schreiber and Rowley ) have identified immunosuppressive cells of mesenchymal origin in mice comprising 2% of the tumor stromal cell population. They were identified by expression of the fibroblast activation protein–α. Deletion of these cells in lung or pancreatic cancers in mice allowed successful therapeutic vaccination against the tumors, which was dependent on the adaptive immune system and the cytokines interferon-γ and tumor necrosis factor–α. These findings reveal that multiple cell types contribute to the immunosuppressive tumor microenvironment and will inform therapeutic cancer vaccine design.