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Cell
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Sep 10, 2015

Volume 162Issue 6p1171-1434
Open Archive
On the cover: Our immune system can recognize and attack cancer cells, but the tumor microenvironment is generally immunosuppressive. Ho et al. (pp. 1217–1228) demonstrate that nutrient deprivation of activated T cells is a form of immunosuppression in tumors and that metabolic rewiring of T cells can enhance anti-tumor immune responses. Chang et al. (pp. 1229–1241) find that checkpoint blockade therapy can restore glucose and reduce glycolysis in tumor cells, providing T cells with the necessary nutrients to fight tumor progression. Kleffel et al. (pp. 1242–1256) show that PD-1/PD-L1 signaling has intrinsic functions within tumor cell subpopulations to promote tumor growth. This image entitled “Cancer: The Beautiful Assassin” illustrates the complexity of the tumor microenvironment and the multiple cell types contained within. Artwork created by Lynn Han (for Ho et al.)....
On the cover: Our immune system can recognize and attack cancer cells, but the tumor microenvironment is generally immunosuppressive. Ho et al. (pp. 1217–1228) demonstrate that nutrient deprivation of activated T cells is a form of immunosuppression in tumors and that metabolic rewiring of T cells can enhance anti-tumor immune responses. Chang et al. (pp. 1229–1241) find that checkpoint blockade therapy can restore glucose and reduce glycolysis in tumor cells, providing T cells with the necessary nutrients to fight tumor progression. Kleffel et al. (pp. 1242–1256) show that PD-1/PD-L1 signaling has intrinsic functions within tumor cell subpopulations to promote tumor growth. This image entitled “Cancer: The Beautiful Assassin” illustrates the complexity of the tumor microenvironment and the multiple cell types contained within. Artwork created by Lynn Han (for Ho et al.).

Leading Edge

In This Issue

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  • Making a Difference in Pain

    Sexual dimorphism can be seen at many levels across the animal kingdom. In humans, it is still surrounded by much controversy and myth. While many sex-specific differences are remarkably obvious, others are subtle, complex, or even puzzling. Psychological and socio-cultural factors can also play a role by heavily influencing the perception of these differences. Take pain, for instance.

Obituary

  • Chris Marshall (1949–2015)

    • Peter W.J. Rigby,
    • Robin A. Weiss
    Chris Marshall, who died on August 8 at age 66, was a world-renowned cell biologist best known for his pioneering contributions to oncogene research and to cell signaling via GTPases, especially to our understanding of tumor cell signaling through the Ras-Raf-Mek-Erk pathway. He spent the whole of his independent research career at the Chester Beatty Laboratories of the Institute of Cancer Research (ICR) in London, where he was Professor of Cell Biology and Head of the Division of Cancer Biology.

Commentary

  • A Well-Hung Horse: Sired by Knowledge and Imagination

    • Joseph L. Goldstein
    For more than a century, historians of science have been spinning a philosophical roulette wheel, pondering which is more important in the creative process: imagination or knowledge. The most original scientists (and artists) in our day discover newness by blending existing knowledge with imaginative thinking.

BenchMarks

  • Deciphering the DNA Damage Response

    • James E. Haber
    This year’s Albert Lasker Basic Medical Research Award honors Evelyn Witkin and Stephen J. Elledge, two pioneers in elucidating the DNA damage response, whose contributions span more than 40 years.
  • Releasing the Brakes on Cancer Immunotherapy

    • Dan R. Littman
    This year’s Lasker∼DeBakey Clinical Research Award goes to James Allison for discovering that antibody blockade of the T cell molecule CTLA-4 unleashes the body’s immune response against malignant tumors. This has led to development of multiple “immune checkpoint therapies” that are prolonging and saving the lives of thousands of cancer patients.

Stories

  • Beginner’s Luck

    • Evelyn Witkin
    On June 5, 1944, I discovered a radiation-resistant mutant of E. coli in my first experiment at the Cold Spring Harbor laboratories. That’s where the new field of bacterial genetics was germinating. I was a Columbia University graduate student, there to learn how to handle E. coli so I could do my doctoral research with bacteria.
  • Accidents and Damage Control

    • Stephen J. Elledge
    My work uncovering the eukaryotic DNA damage response pathway is a tale of serendipity and four amino acids. After graduate school at MIT, I joined Ron Davis’s lab as a post-doc initially to work on plants but became interested in developing gene-targeting methods for mammals. I had reasoned, naively, that the protein responsible for homologous recombination in mammals would be related to the master regulator of recombination in bacteria, recA. RecA protein had the ability to initiate recombination in vitro on its own using ssDNA and ATP.
  • Checkpoints

    • James P. Allison
    I cup the harmonica and start playing with the rest of the band—The Checkpoints. The crowd gets on their feet, cheering and dancing to “King Bee.” It was the 2015 annual American Society of Clinical Oncology (ASCO) meeting. The Society for Immunotherapy of Cancer had organized for us to play one night at the House of Blues in Chicago. The place was packed. Immunologists, oncologists, radiologists, pathologists, journalists, and patients attended our gig. They were celebrating. Not just the skills of the band members—all cancer researchers—but the field of cancer immunotherapy and the amazing clinical successes that were just announced at that ASCO meeting.

Previews

  • Nutrient Competition: A New Axis of Tumor Immunosuppression

    • Madhusudhanan Sukumar,
    • Rahul Roychoudhuri,
    • Nicholas P. Restifo
    It is thought that cancer cells engage in Warburg metabolism to meet intrinsic biosynthetic requirements of cell growth and proliferation. Papers by Chang et al. and Ho et al. show that Warburg metabolism enables tumor cells to restrict glucose availability to T cells, suppressing anti-tumor immunity.
  • Single-Cell Analysis: The Differences That Kill

    • Savaş Tay
    Using single-cell RNA sequencing, Avraham et al. investigate how variability in macrophage response to infection is controlled by variability within the pathogen population. They find that heterogeneous expression of the Salmonella virulence factor PhoP and subsequent cell-wall modifications lead to the bimodal induction of the interferon-response in infected macrophages.
  • Helping the Help for CD8+ T Cell Responses

    • Sebastian Amigorena
    Eickhoff et al. and Hor et al. use time-lapse intravital microscopy to show an unexpected choreography of CD4+ and CD8+ T cells “dancing” between different dendritic cell sub-populations during priming of cytotoxic immune responses to viruses.
  • Melatonin Lulling Th17 Cells to Sleep

    • Jacob S. Lee,
    • Daniel J. Cua
    In this issue, Farez et al. report that the circadian hormone melatonin, whose levels vary with seasonal changes in night length, shifts the immune response toward an anti-inflammatory state that may explain the seasonal variability of multiple sclerosis disease activity.
  • The Touching Tail of a Mechanotransduction Channel

    • Zachary A. Knecht,
    • Rachelle Gaudet,
    • Paul A. Garrity
    In mechanotransduction, sensory receptors convert force into electrical signals to mediate such diverse functions as touch, pain, and hearing. In this issue of Cell, Zhang et al. present evidence that the fly NompC channel senses mechanical stimuli using its N-terminal tail as a tether between the cell membrane and microtubules.

Articles

  • Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses

    • Ping-Chih Ho,
    • Jessica Dauz Bihuniak,
    • Andrew N. Macintyre,
    • Matthew Staron,
    • Xiaojing Liu,
    • Robert Amezquita,
    • Yao-Chen Tsui,
    • Guoliang Cui,
    • Goran Micevic,
    • Jose C. Perales,
    • Steven H. Kleinstein,
    • E. Dale Abel,
    • Karl L. Insogna,
    • Stefan Feske,
    • Jason W. Locasale,
    • Marcus W. Bosenberg,
    • Jeffrey C. Rathmell,
    • Susan M. Kaech
    High rates of tumor cell glycolysis suppress intratumoral T cell function by depriving T cells of glucose and the downstream metabolite phosphoenolpyruvate (PEP), which is necessary for maximal Ca2+ -NFAT signaling in T cells. Metabolic rewiring of T cells to generate PEP in glucose-poor conditions improves their anti-tumor responses.
  • Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression

    • Chih-Hao Chang,
    • Jing Qiu,
    • David O’Sullivan,
    • Michael D. Buck,
    • Takuro Noguchi,
    • Jonathan D. Curtis,
    • Qiongyu Chen,
    • Mariel Gindin,
    • Matthew M. Gubin,
    • Gerritje J.W. van der Windt,
    • Elena Tonc,
    • Robert D. Schreiber,
    • Edward J. Pearce,
    • Erika L. Pearce
    Glucose consumption by antigenic tumors can metabolically restrict T cells, directly dampening their effector function and allowing tumor progression. Checkpoint blockade therapy may correct this resource imbalance through a direct effect in the tumor cells.
  • Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth

    • Sonja Kleffel,
    • Christian Posch,
    • Steven R. Barthel,
    • Hansgeorg Mueller,
    • Christoph Schlapbach,
    • Emmanuella Guenova,
    • Christopher P. Elco,
    • Nayoung Lee,
    • Vikram R. Juneja,
    • Qian Zhan,
    • Christine G. Lian,
    • Rahel Thomi,
    • Wolfram Hoetzenecker,
    • Antonio Cozzio,
    • Reinhard Dummer,
    • Martin C. Mihm Jr.,
    • Keith T. Flaherty,
    • Markus H. Frank,
    • George F. Murphy,
    • Arlene H. Sharpe,
    • Thomas S. Kupper,
    • Tobias Schatton
    PD-1/PD-L1 signaling has cell-intrinsic functions in certain types of mouse and human tumors, boosting cancer growth and promoting tumorigenesis. This suggests that immunotherapy with PD-1 blockers may produce an effect on tumor growth that is separate from their effect on the immune response.
  • Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity

    • Santiago Zelenay,
    • Annemarthe G. van der Veen,
    • Jan P. Böttcher,
    • Kathryn J. Snelgrove,
    • Neil Rogers,
    • Sophie E. Acton,
    • Probir Chakravarty,
    • Maria Romina Girotti,
    • Richard Marais,
    • Sergio A. Quezada,
    • Erik Sahai,
    • Caetano Reis e Sousa
    Cyclooxygenase-driven prostaglandin E2, produced by a variety of tumors, drives malignant growth through successful evasion of type I interferon and/or T-cell-dependent tumor elimination. A remarkable synergy between cyclooxygenase inhibitors and checkpoint blockade immunotherapy results in tumor eradication.
  • Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance

    • Willy Hugo,
    • Hubing Shi,
    • Lu Sun,
    • Marco Piva,
    • Chunying Song,
    • Xiangju Kong,
    • Gatien Moriceau,
    • Aayoung Hong,
    • Kimberly B. Dahlman,
    • Douglas B. Johnson,
    • Jeffrey A. Sosman,
    • Antoni Ribas,
    • Roger S. Lo
    Resistance to targeted therapies in melanoma is associated with acquisition of highly recurrent non-genomic alterations as well as changes in the immune landscape of the tumor that may result in cross-resistance to salvage anti-PD-1/PD-L1 immunotherapy.
  • Reversible, Specific, Active Aggregates of Endogenous Proteins Assemble upon Heat Stress

    • Edward W.J. Wallace,
    • Jamie L. Kear-Scott,
    • Evgeny V. Pilipenko,
    • Michael H. Schwartz,
    • Pawel R. Laskowski,
    • Alexandra E. Rojek,
    • Christopher D. Katanski,
    • Joshua A. Riback,
    • Michael F. Dion,
    • Alexander M. Franks,
    • Edoardo M. Airoldi,
    • Tao Pan,
    • Bogdan A. Budnik,
    • D. Allan Drummond
    The aggregates of endogenous proteins triggered by heat stress in yeast are reversible. Rather than representing irreparably misfolded proteins destined for degradation, they can maintain activity and re-solubilize, suggesting an adaptive strategy underlying aggregation.
  • HNRNPA2B1 Is a Mediator of m6A-Dependent Nuclear RNA Processing Events

    • Claudio R. Alarcón,
    • Hani Goodarzi,
    • Hyeseung Lee,
    • Xuhang Liu,
    • Saeed Tavazoie,
    • Sohail F. Tavazoie
    The RNA-binding protein HNRNPA2B1 is a nuclear “reader” of the m6A mark, acting as an adaptor that recruits the Microprocessor complex to a subset of precursor miRNAs, facilitating their processing into mature miRNAs.
  • Pathogen Cell-to-Cell Variability Drives Heterogeneity in Host Immune Responses

    • Roi Avraham,
    • Nathan Haseley,
    • Douglas Brown,
    • Cristina Penaranda,
    • Humberto B. Jijon,
    • John J. Trombetta,
    • Rahul Satija,
    • Alex K. Shalek,
    • Ramnik J. Xavier,
    • Aviv Regev,
    • Deborah T. Hung
    Functional heterogeneity in the response of host cells to infection is driven by cell-to-cell transcriptional variations in the population of infecting pathogens.
  • Robust Anti-viral Immunity Requires Multiple Distinct T Cell-Dendritic Cell Interactions

    • Sarah Eickhoff,
    • Anna Brewitz,
    • Michael Y. Gerner,
    • Frederick Klauschen,
    • Karl Komander,
    • Hiroaki Hemmi,
    • Natalio Garbi,
    • Tsuneyasu Kaisho,
    • Ronald Nathan Germain,
    • Wolfgang Kastenmüller
    During the course of a viral infection, CD4+ and CD8+ T lymphocyte activation is initially separated spatially, but a subset of dendritic cells acts as a platform to orchestrate their communication to optimize CD8+ T cell expansion and memory function.
  • Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses

    • Mauricio F. Farez,
    • Ivan D. Mascanfroni,
    • Santiago P. Méndez-Huergo,
    • Ada Yeste,
    • Gopal Murugaiyan,
    • Lucien P. Garo,
    • María E. Balbuena Aguirre,
    • Bonny Patel,
    • María C. Ysrraelit,
    • Chen Zhu,
    • Vijay K. Kuchroo,
    • Gabriel A. Rabinovich,
    • Francisco J. Quintana,
    • Jorge Correale
    Melatonin affects the differentiation and function of effector and regulatory T cells in vitro and in vivo, representing an environmental cue that contributes to the seasonality of multiple sclerosis relapses and a potential target for therapeutic intervention in immune-mediated diseases.
  • A Mechanism for Sustained Cellulose Synthesis during Salt Stress

    • Anne Endler,
    • Christopher Kesten,
    • René Schneider,
    • Yi Zhang,
    • Alexander Ivakov,
    • Anja Froehlich,
    • Norma Funke,
    • Staffan Persson
    Plant biomass provides us with many essential products and an understanding for how it is synthesized is therefore important to support human activities. A central element to plant biomass is the cell wall; a cellular exoskeleton in which the glucan-based polymer cellulose is a prominent component. This paper identifies a protein family whose members are components of the cellulose synthesizing machinery in plants and reveals a mechanism for how plants maintain their biomass producing capacity during saline conditions.
  • Targeting of Fn14 Prevents Cancer-Induced Cachexia and Prolongs Survival

    • Amelia J. Johnston,
    • Kate T. Murphy,
    • Laura Jenkinson,
    • David Laine,
    • Kerstin Emmrich,
    • Pierre Faou,
    • Ross Weston,
    • Krishnath M. Jayatilleke,
    • Jessie Schloegel,
    • Gert Talbo,
    • Joanne L. Casey,
    • Vita Levina,
    • W. Wei-Lynn Wong,
    • Helen Dillon,
    • Tushar Sahay,
    • Joan Hoogenraad,
    • Holly Anderton,
    • Cathrine Hall,
    • Pascal Schneider,
    • Maria Tanzer,
    • Michael Foley,
    • Andrew M. Scott,
    • Paul Gregorevic,
    • Spring Yingchun Liu,
    • Linda C. Burkly,
    • Gordon S. Lynch,
    • John Silke,
    • Nicholas J. Hoogenraad
    Antibodies against the TWEAK receptor Fn14 prevent tumor-induced cachexia and extend lifespan by inhibiting weight loss and inflammation, although having only moderate effects on tumor growth.
  • Broadly Neutralizing Antibody 8ANC195 Recognizes Closed and Open States of HIV-1 Env

    • Louise Scharf,
    • Haoqing Wang,
    • Han Gao,
    • Songye Chen,
    • Alasdair W. McDowall,
    • Pamela J. Bjorkman
    Broadly neutralizing antibodies against the HIV-1 envelope trimer are under consideration for therapeutic administration. Structural analysis of one such antibody, 8ANC195, uncovers a previously unseen conformation of the envelope protein and suggests that 8ANC195 binding partially closes the host receptor-bound open envelope trimer conformation.
  • Ankyrin Repeats Convey Force to Gate the NOMPC Mechanotransduction Channel

    • Wei Zhang,
    • Li E. Cheng,
    • Maike Kittelmann,
    • Jiefu Li,
    • Maja Petkovic,
    • Tong Cheng,
    • Peng Jin,
    • Zhenhao Guo,
    • Martin C. Göpfert,
    • Lily Yeh Jan,
    • Yuh Nung Jan
    Study of mechanotransduction channel NOMPC reveals a tether mechanism of mechanogating in which the N-terminal ARs of NOMPC form a tether linking the channel and the microtubules that convey force exerted via cell deformation to gate the channel and activate touch-sensitive neurons.
  • Hypothalamic UDP Increases in Obesity and Promotes Feeding via P2Y6-Dependent Activation of AgRP Neurons

    • Sophie M. Steculorum,
    • Lars Paeger,
    • Stephan Bremser,
    • Nadine Evers,
    • Yvonne Hinze,
    • Marco Idzko,
    • Peter Kloppenburg,
    • Jens C. Brüning
    The UDP-selective P2Y6 receptor controls orexigenic AgRP neurons and food intake regulation. The pathway is deregulated in obesity, making P2Y6 a potential target for treatment.
  • Dopamine Is Required for the Neural Representation and Control of Movement Vigor

    • Babita Panigrahi,
    • Kathleen A. Martin,
    • Yi Li,
    • Austin R. Graves,
    • Alison Vollmer,
    • Lars Olson,
    • Brett D. Mensh,
    • Alla Y. Karpova,
    • Joshua T. Dudman
    Movement vigor, reduced in Parkinson’s disease, is regulated by dopamine-dependent activity in the striatum.

Erratum

Timelines

  • Timeline: Sending Out an SOS

    • Brian Plosky
    “Walked out this morning, don't believe what I saw/Hundred billion bottles washed up on the shore”–Sting. When looking at the myriad changes in the transcriptome and proteome during the response to DNA damage, it seems like hundreds of billions of bottles might be washing across your computer screen. Focusing on just the proteomics datasets describing the dynamics of protein modifications that occur in response to DNA damage, there are tens of thousands of post-translational modifications, which you can read about in many papers, including several from Stephen Elledge, one of the recipients of the 2015 Albert Lasker Basic Medical Research Award.
  • Timeline: Checkpoint Blockade

    • Joao Monteiro
    Immune checkpoint therapy, targeting inhibitory pathways in T cells to unleash antitumor immune responses, has led to amazing advances in the clinical care of patients with highly aggressive and otherwise-untreatable cancers. Paraphrasing Jim Allison, the recipient of the 2015 Lasker-DeBakey Clinical Medical Research Award, before we were able to successfully use the immune system to treat cancer, we had to understand the inner workings of the immune response. This timeline highlights key contributions over the past 30 years that constituted essential steps toward the concept of immune checkpoint therapy.
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