IL-15 is a component of the inflammatory milieu in the tumor microenvironment promoting antitumor responses.

Abstract:

:Previous studies have provided evidence that IL-15 expression within human tumors is crucial for optimal antitumor responses; however, the regulation of IL-15 within the tumor microenvironment (TME) is unclear. We report herein, in analyses of mice implanted with various tumor cell lines, soluble IL-15/IL-15Rα complexes (sIL-15 complexes) are abundant in the interstitial fluid of tumors with expression preceding the infiltration of tumor-infiltrating lymphocytes. Moreover, IL-15 as well as type I IFN, which regulates IL-15, was required for establishing normal numbers of CD8 T cells and natural killer cells in tumors. Depending on tumor type, both the tumor and the stroma are sources of sIL-15 complexes. In analyses of IL-15 reporter mice, most myeloid cells in the TME express IL-15 with CD11b+Ly6Chi cells being the most abundant, indicating there is a large source of IL-15 protein in tumors that lies sequestered within the tumor stroma. Despite the abundance of IL-15-expressing cells, the relative levels of sIL-15 complexes are low in advanced tumors but can be up-regulated by local stimulator of IFN genes (STING) activation. Furthermore, while treatment of tumors with STING agonists leads to tumor regression, optimal STING-mediated immunity and regression of distant secondary tumors required IL-15 expression. Overall, our study reveals the dynamic regulation of IL-15 in the TME and its importance in antitumor immunity. These findings provide insight into an unappreciated attribute of the tumor landscape that contributes to antitumor immunity, which can be manipulated therapeutically to enhance antitumor responses.

authors

Santana Carrero RM,Beceren-Braun F,Rivas SC,Hegde SM,Gangadharan A,Plote D,Pham G,Anthony SM,Schluns KS

doi

10.1073/pnas.1814642116

subject

Has Abstract

pub_date

2019-01-08 00:00:00

pages

599-608

issue

2

eissn

0027-8424

issn

1091-6490

pii

1814642116

journal_volume

116

pub_type

杂志文章
  • Stochastic model of protein-protein interaction: why signaling proteins need to be colocalized.

    abstract::Colocalization of proteins that are part of the same signal transduction pathway via compartmentalization, scaffold, or anchor proteins is an essential aspect of the signal transduction system in eukaryotic cells. If interaction must occur via free diffusion, then the spatial separation between the sources of the two ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0401314101

    authors: Batada NN,Shepp LA,Siegmund DO

    更新日期:2004-04-27 00:00:00

  • Selfish supernumerary chromosome reveals its origin as a mosaic of host genome and organellar sequences.

    abstract::Supernumerary B chromosomes are optional additions to the basic set of A chromosomes, and occur in all eukaryotic groups. They differ from the basic complement in morphology, pairing behavior, and inheritance and are not required for normal growth and development. The current view is that B chromosomes are parasitic e...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1204237109

    authors: Martis MM,Klemme S,Banaei-Moghaddam AM,Blattner FR,Macas J,Schmutzer T,Scholz U,Gundlach H,Wicker T,Šimková H,Novák P,Neumann P,Kubaláková M,Bauer E,Haseneyer G,Fuchs J,Doležel J,Stein N,Mayer KF,Houben A

    更新日期:2012-08-14 00:00:00

  • A metabolic indicator of photoperiodic timing.

    abstract::Characteristics of CO2 output patterns of axenic cultures of Lemna perpusilla are being sought that would serve as biochemically definable indicators of the crucial photoperiodic events during inductive light/dark schedules, using cycles with skeleton main light periods and overall periodicities of 24 hr. As the lengt...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.73.2.501

    authors: Hillman WS

    更新日期:1976-02-01 00:00:00

  • Structural gene for beta-nerve growth factor not defective in familial dysautonomia.

    abstract::The developmental loss of neurons in sympathetic, sensory, and some parasympathetic ganglia in familial dysautonomia suggests an inherited defect in the action of beta-nerve growth factor (beta-NGF). The role of this growth factor in dysautonomia has been difficult to resolve as there is no known source of authentic h...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.81.13.4213

    authors: Breakefield XO,Orloff G,Castiglione C,Coussens L,Axelrod FB,Ullrich A

    更新日期:1984-07-01 00:00:00

  • Primary structure and tissue distribution of the orphanin FQ precursor.

    abstract::The heptadecapeptide orphanin FQ (OFQ) is a recently discovered neuropeptide that exhibits structural features reminiscent of the opioid peptides and that is an endogenous ligand to a G protein-coupled receptor sequentially related to the opioid receptors. We have cloned both the human and rat cDNAs encoding the OFQ p...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.93.16.8677

    authors: Nothacker HP,Reinscheid RK,Mansour A,Henningsen RA,Ardati A,Monsma FJ Jr,Watson SJ,Civelli O

    更新日期:1996-08-06 00:00:00

  • Unrepaired clustered DNA lesions induce chromosome breakage in human cells.

    abstract::Clustered DNA damage induced by ionizing radiation is refractory to repair and may trigger carcinogenic events for reasons that are not well understood. Here, we used an in situ method to directly monitor induction and repair of clustered DNA lesions in individual cells. We showed, consistent with biophysical modeling...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1016045108

    authors: Asaithamby A,Hu B,Chen DJ

    更新日期:2011-05-17 00:00:00

  • Are DNA spacers relics of gene amplification events?

    abstract::The genome of a thermophilic fungus, Thermomyces lanuginosus, contains a tandemly arranged cluster of sequences that are approximately equal to 50% homologous with the cytoplasmic 5S RNA and that are selectable by hybridization techniques. Unlike typical pseudogenes, these sequences are not truncated; rather, they bea...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.81.6.1768

    authors: Wong WM,Abrahamson JL,Nazar RN

    更新日期:1984-03-01 00:00:00

  • The spread of attention across modalities and space in a multisensory object.

    abstract::Attending to a stimulus is known to enhance the neural responses to that stimulus. Recent experiments on visual attention have shown that this modulation can have object-based characteristics, such that, when certain parts of a visual object are attended, other parts automatically also receive enhanced processing. Her...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0507704102

    authors: Busse L,Roberts KC,Crist RE,Weissman DH,Woldorff MG

    更新日期:2005-12-20 00:00:00

  • A transcript profiling approach reveals an epicatechin-specific glucosyltransferase expressed in the seed coat of Medicago truncatula.

    abstract::Expression of the Arabidopsis TRANSPARENT TESTA 2 (TT2) MYB family transcription factor leads to massive accumulation of proanthocyanidins (PAs) in hairy roots of Medicago truncatula. Microarray analysis showed that TT2 induces genes for flavonoid/PA biosynthesis, transcription factors, and a large number of genes of ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0805954105

    authors: Pang Y,Peel GJ,Sharma SB,Tang Y,Dixon RA

    更新日期:2008-09-16 00:00:00

  • Reduction to homozygosity involving p53 in esophageal cancers demonstrated by the polymerase chain reaction.

    abstract::Loss of heterozygosity affecting chromosome 17p has been detected at high frequencies in a variety of human tumors, including cancers of the colon, breast, lung, and brain. One presumed target of these losses is p53, a tumor suppressor gene located on 17p. To our knowledge, loss of heterozygosity has not yet been repo...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.88.11.4976

    authors: Meltzer SJ,Yin J,Huang Y,McDaniel TK,Newkirk C,Iseri O,Vogelstein B,Resau JH

    更新日期:1991-06-01 00:00:00

  • SraL sRNA interaction regulates the terminator by preventing premature transcription termination of rho mRNA.

    abstract::Transcription termination is a critical step in the control of gene expression. One of the major termination mechanisms is mediated by Rho factor that dissociates the complex mRNA-DNA-RNA polymerase upon binding with RNA polymerase. Rho promotes termination at the end of operons, but it can also terminate transcriptio...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1811589116

    authors: Silva IJ,Barahona S,Eyraud A,Lalaouna D,Figueroa-Bossi N,Massé E,Arraiano CM

    更新日期:2019-02-19 00:00:00

  • Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade immunotherapy.

    abstract::Cancer relapse after surgery is a common occurrence, most frequently resulting from the outgrowth of minimal residual disease in the form of metastases. We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade as an adjunctive immunotherapy to reduce metastatic relapse after prima...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.96.26.15074

    authors: Kwon ED,Foster BA,Hurwitz AA,Madias C,Allison JP,Greenberg NM,Burg MB

    更新日期:1999-12-21 00:00:00

  • CCAAT/enhancer-binding protein δ facilitates bacterial dissemination during pneumococcal pneumonia in a platelet-activating factor receptor-dependent manner.

    abstract::CCAAT/enhancer-binding protein δ (C/EBPδ) recently emerged as an essential player in the inflammatory response to bacterial infections. C/EBPδ levels increase rapidly after a proinflammatory stimulus, and increasing C/EBPδ levels seem to be indispensable for amplification of the inflammatory response. Here we aimed to...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1202641109

    authors: Duitman J,Schouten M,Groot AP,Borensztajn KS,Daalhuisen JB,Florquin S,van der Poll T,Spek CA

    更新日期:2012-06-05 00:00:00

  • Free radical functionalization of surfaces to prevent adverse responses to biomedical devices.

    abstract::Immobilizing a protein, that is fully compatible with the patient, on the surface of a biomedical device should make it possible to avoid adverse responses such as inflammation, rejection, or excessive fibrosis. A surface that strongly binds and does not denature the compatible protein is required. Hydrophilic surface...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1103277108

    authors: Bilek MM,Bax DV,Kondyurin A,Yin Y,Nosworthy NJ,Fisher K,Waterhouse A,Weiss AS,dos Remedios CG,McKenzie DR

    更新日期:2011-08-30 00:00:00

  • Photophosphorylation by monomolecular films at an air-water interface.

    abstract::An acetone extract of chloroplast particles, when layered on an aqueous surface, exhibited light-dependent phosphorylation. Studies with the firefly-tail enzyme assay, as well as with (32)P-labeled inorganic phosphate, show an initial release of adenosine triphosphate (a step that is apparently only light-triggered), ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.70.1.50

    authors: McPhee J,Brody SS

    更新日期:1973-01-01 00:00:00

  • Spontaneous liposome formation induced by grafted poly(ethylene oxide) layers: theoretical prediction and experimental verification.

    abstract::Spontaneous liposome formation is predicted in binary mixtures of fluid phase phospholipids and poly(n)ethylene oxide (PEO)-bearing lipids by using single chain mean field theory. The range of stability of the spontaneous liposomes is determined as a function of percentage of PEO-conjugated lipids and polymer molecula...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.3.1032

    authors: Szleifer I,Gerasimov OV,Thompson DH

    更新日期:1998-02-03 00:00:00

  • cAMP post-transcriptionally diminishes the abundance of adrenodoxin reductase mRNA.

    abstract::Adrenodoxin reductase (AR; ferridoxin: NADP+ oxidoreductase, EC 1.18.1.2) is a flavoprotein that mediates electron transport from NADPH to all known mitochondrial forms of cytochrome P450. AR mRNA was found in all human adult and fetal tissues examined; however, it was vastly more abundant in tissues that synthesize s...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.89.9.4099

    authors: Brentano ST,Black SM,Lin D,Miller WL

    更新日期:1992-05-01 00:00:00

  • Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons.

    abstract::Convergent evidence has revealed an association between insulin resistance and Alzheimer's disease (AD), and the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, rosiglitazone, an insulin sensitizer and mitochondrial activator, improves cognition in patients with early or mild-to-moderate AD. Apo...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0709906104

    authors: Brodbeck J,Balestra ME,Saunders AM,Roses AD,Mahley RW,Huang Y

    更新日期:2008-01-29 00:00:00

  • A prokaryotic membrane anchor sequence: carboxyl terminus of bacteriophage f1 gene III protein retains it in the membrane.

    abstract::Gene III protein of bacteriophage f1 is inserted into the host cell membrane where it is assembled into phage particles. A truncated form of gene III protein, encoded by a recombinant plasmid and lacking the carboxyl terminus, does not remain in the membrane but instead appears to slip through it. Fusion of a hydropho...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.79.17.5200

    authors: Boeke JD,Model P

    更新日期:1982-09-01 00:00:00

  • Conscious recollection and the human hippocampal formation: evidence from positron emission tomography.

    abstract::We used positron emission tomography (PET) to examine the role of the hippocampal formation in implicit and explicit memory. Human volunteers studied a list of familiar words, and then they either provided the first word that came to mind in response to three-letter cues (implicit memory) or tried to recall studied wo...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.93.1.321

    authors: Schacter DL,Alpert NM,Savage CR,Rauch SL,Albert MS

    更新日期:1996-01-09 00:00:00

  • Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2.

    abstract::In healthy adults, activation of γ-aminobutyric acid (GABA)(A) and glycine receptors inhibits neurons as a result of low intracellular chloride concentration ([Cl(-)](i)), which is maintained by the potassium-chloride cotransporter KCC2. A reduction of KCC2 expression or function is implicated in the pathogenesis of s...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1213680110

    authors: Bos R,Sadlaoud K,Boulenguez P,Buttigieg D,Liabeuf S,Brocard C,Haase G,Bras H,Vinay L

    更新日期:2013-01-02 00:00:00

  • Automated prediction of protein function and detection of functional sites from structure.

    abstract::Current structural genomics projects are yielding structures for proteins whose functions are unknown. Accordingly, there is a pressing requirement for computational methods for function prediction. Here we present PHUNCTIONER, an automatic method for structure-based function prediction using automatically extracted f...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0404569101

    authors: Pazos F,Sternberg MJ

    更新日期:2004-10-12 00:00:00

  • Assembly of rod-shaped virus in vitro: reconstitution with cucumber green mottle mosaic virus protein and tobacco mosaic virus RNA.

    abstract::In vitro assembly of tobacco mosaic virus (TMV) from its constituent RNA and protein occurs in two steps: formation of the initial complex by interaction of the 5'-end of TMV-RNA with 20S protein aggregate, and growth of the helical rod by sequential addition of protein subunits.Such a process was also observed in the...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.69.12.3680

    authors: Ono T,Inoue H,Okada Y

    更新日期:1972-12-01 00:00:00

  • Silkworms transformed with chimeric silkworm/spider silk genes spin composite silk fibers with improved mechanical properties.

    abstract::The development of a spider silk-manufacturing process is of great interest. However, there are serious problems with natural manufacturing through spider farming, and standard recombinant protein production platforms have provided limited progress due to their inability to assemble spider silk proteins into fibers. T...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1109420109

    authors: Teulé F,Miao YG,Sohn BH,Kim YS,Hull JJ,Fraser MJ Jr,Lewis RV,Jarvis DL

    更新日期:2012-01-17 00:00:00

  • A biosensor assay for studying ligand-membrane receptor interactions: binding of antibodies and HIV-1 Env to chemokine receptors.

    abstract::The HIV envelope (Env) protein mediates entry into cells by binding CD4 and an appropriate coreceptor, which triggers structural changes in Env that lead to fusion between the viral and cellular membranes. The major HIV-1 coreceptors are the seven transmembrane domain chemokine receptors CCR5 and CXCR4. The type of co...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.190274097

    authors: Hoffman TL,Canziani G,Jia L,Rucker J,Doms RW

    更新日期:2000-10-10 00:00:00

  • MRIT, a novel death-effector domain-containing protein, interacts with caspases and BclXL and initiates cell death.

    abstract::Activation of the cascade of proteolytic caspases has been identified as the final common pathway of apoptosis in diverse biological systems. We have isolated a gene, termed MRIT, that possesses overall sequence homology to FLICE (MACH), a large prodomain caspase that links the aggregated complex of the death domain r...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.94.21.11333

    authors: Han DK,Chaudhary PM,Wright ME,Friedman C,Trask BJ,Riedel RT,Baskin DG,Schwartz SM,Hood L

    更新日期:1997-10-14 00:00:00

  • T lymphocyte response to H-2 mutants: cytotoxic effectors are Ly-1+2+.

    abstract::The lymphocyte differentiation (Ly) antigen phenotype of cytotoxic effector T cells specific for H-2 mutant alloantigens was determined. Cytotoxic effectors generated in primary mixed lymphocyte culture and specific for H-2Kba and H-2Dda alloantigens are sensitive to both anti-Ly-1 and anti-Ly-2 serum plus complement....

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.76.7.3455

    authors: Wettstein PJ,Bailey DW,Mobraaten LE,Klein J,Frelinger JA

    更新日期:1979-07-01 00:00:00

  • Structural plasticity of an aminoacyl-tRNA synthetase active site.

    abstract::Recently, tRNA aminoacyl-tRNA synthetase pairs have been evolved that allow one to genetically encode a large array of unnatural amino acids in both prokaryotic and eukaryotic organisms. We have determined the crystal structures of two substrate-bound Methanococcus jannaschii tyrosyl aminoacyl-tRNA synthetases that ch...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0601756103

    authors: Turner JM,Graziano J,Spraggon G,Schultz PG

    更新日期:2006-04-25 00:00:00

  • Anti-idiotypic antibodies to anti-HLA receptors induced by pregnancy.

    abstract::We have previously shown that lymphoblasts alloactivated in vitro acquire the capacity of stimulating the autologous mixed lymphocyte response. This response is anti-idiotypic in nature because lymphocytes so primed display accelerated memory responses only when restimulated by autologous lymphoblasts that have been a...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.80.3.830

    authors: Suciu-Foca N,Reed E,Rohowsky C,Kung P,King DW

    更新日期:1983-02-01 00:00:00

  • Association of selected persistent organic pollutants in the placenta with the risk of neural tube defects.

    abstract::Persistent organic pollutants (POPs) have been associated with a wide range of adverse health effects. Our case-control study was performed to explore the association between placental levels of selected POPs and risks for neural tube defects (NTDs) in a Chinese population with a high prevalence of NTDs. Cases include...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1105209108

    authors: Ren A,Qiu X,Jin L,Ma J,Li Z,Zhang L,Zhu H,Finnell RH,Zhu T

    更新日期:2011-08-02 00:00:00