THE INTERNATIONAL WEEKLY JOURNAL OF SCIENCE
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`DEC 29 2011
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`ONOF REMOVE FROM
`Bent PERIODICALS
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`Genome & Co.v. Univ. of Chicago
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`UNIV. CHICAGO EX. 2036
`The newsmakersof the year pase4s7
`
`_ PHYSICS
`REBOOTING
`{ticlecould tiestring
`
`eory to standard model
`PAGE 415
`
`THE CROP
`CREAM OF
`Editors’pickof2011’s
`
`outstandingarticles
`PAGE 468
`
`DIRECTORY.2012
`EV
`Yourguidetoglobalscientific
`
`events and courses
`BACK PAGES & NATUREEVENTS.COM
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`© NATURE.COM/NATU
`22/29 December 2011
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` CONTENTS
`
`22/29 December2011 / Vol 480 / Issue No 7378
`
`EDITORIAL
`4l4/ Ten for 2011
`Capturing the characters of the year
`
`NEWS
`426 2011 in review.
`_/Fromseandals to fallout‘and all
`points between
`430 Images oftheyear’
`
`FEATURES
`//
`//////
`437 /Nature’s10°///
`Whowerethe people whomade a
`mark on the past’12months?
`
`1/2011 1N REVIEW
`
`theyearin science
`
`365DAYS:
`
`COMMENT /
`447 The new history
`Philip Ball
`The major events of 2011 were
`driven by complexity as well as
`social media and‘globalization
`/NEWS & VIEWS
`468° Editors’ choice
`Alook back at some of the
`highlights from this year’s
`News & Views.
`
`Coverandillustrations by Carl DeTorres
`
`SD aature.com/2011
`
`THIS WEEK
`
`|
`
`NEWS IN FOCUS
`
`|
`
`COMMENT
`
`EDITORIALS
`413 POLICY
`The morningafter
`The US government was wrongto
`overrule recommendations on Plan B
`
`413
`
`ENVIRONMENT
`Defend the Amazon
`Brazil's attempts to reform forest
`protection must be reworked
`
`WORLD VIEW
`415 Particle physics is at a turning point
`Gordon Kane
`The putative discovery of the Higgs
`bosonis a boonfor string theorists
`
`RESEARCH HIGHLIGHTS
`416 SELECTIONS FROM THE
`SCIENTIFIC LITERATURE
`Mercury's
`magnetosphere/ Egg
`counts / Bacterial
`microtubules / Why
`frogs make music / Lost
`Hox genes / Owning the
`world / Neanderthals
`not up to sniff
`
`
`
`SEVEN DAYS
`418 THE NEWSIN BRIEF
`Fukushimafinally in shutdown / The
`world’s tiniest tetrapod / Vote on
`Brazilian forest postponed / Variome
`initiative under way in China
`
`421 BIOSAFETY
`Altered bird-flu virus raises questions
`about lab security
`423 POLICY
`US budget paves the way for new
`NIH centre
`
`closer to reality
`
`424 ANIMAL RESEARCH
`Report spells out
`toughcriteria for
`NIH-funded chimp
`research
`
`425 POLICY
`US integrity rules edge
`
`449 SCIENCE PUBLISHING
`The paper is not sacred
`Adam Marcus & Ivan Oransky
`Therise in retractions this year argues
`for the broadening of peer review
`
`BOOKS & ARTS
`451 TECHNOLOGY
`Rise of the e-book
`Carl Zimmer
`
`452 FOOD SCIENCE
`With pipette and ladle
`
`
`
`HaroldMcGee a
`
`453 O&A
`The snowflake designer
`Physicist Kenneth Libbrecht takes the
`study of snowflakes to extremes
`455 IN RETROSPECT
`On the Six-Cornered Snowflake
`Philip Ball
`
`CORRESPONDENCE
`457 Leonardo da Vinci's physics / Europe's
`threatened vultures / Thefirst cells
`
`OBITUARY
`458 Lynn Margulis (1938-2011)
`James A Lake
`
`
`FUTURES
`578 Tea withJillian
`Brenda Cooper
`
`
`
`
`
`CAREERS
`
`575 AWARDS
`Conscientious counsellors
`Nature's 2011 mentoring awards go
`Parisienne
`
`576 COLUMN
`Testing the waters
`Postdocs and industry do mix, say
`Christopher Tsang and Michael Fisher
`
`natureevents
`
`
`
`Your guideto global scientific events
`and coursesin 2012
`
`22/29 DECEMBER 2011 |
`
`VOL 480 | NATURE | 407
`
`

`

`CONTENTS
`
`22/29 December 2011 / Vol 480 / Issue No 7378
`
`RESEARCH
`
`REVIEWS
`47|
`ORGANIC CHEMISTRY Rethinking
`amide bond synthesis
`VR Pattabiraman & J W Bode
`
`480
`
`CANCER Cancer immunotherapy
`comesof age
`| Mellman, G Coukos & G Dranoff
`
`ARTICLE
`490
`GENOMICS DNA-binding factors
`shape the mouse methylome at
`distal regulatory regions
`MB Stadleretal.
`
`LETTERS
`496
`ASTRONOMY A compactsystem of small
`planets around a former red-giant star
`S Charpinetet al. SEE N&V P.460
`
`500
`
`504
`
`509
`
`513
`
`516
`
`520
`
`529
`
`530
`
`PHYSICS Orbital excitation blockade and
`algorithmic cooling in quantum gases
`WS Bakr etal. SEE N&V P.463
`
`MATERIALS SCIENCE Tuning charge
`transport in solution-sheared organic
`semiconductors using lattice strain
`G Giri etal.
`
`CLIMATE SCIENCE Forcing of wet phases
`in southeastAfrica overthe past
`17,000 years
`E SchefuB, H Kuhlmann, G Mollenhauer,
`M Prange & J Patzold
`
`PALAEONTOLOGY Lowland-upland
`migration of sauropod dinosaurs during
`the Late Jurassic epoch
`HC Fricke, J Hencecroth & M E Hoerner
`
`ECOLOGY Additive threats from
`pathogens, climate and land-use
`changefor global amphibian diversity
`C Hof, M B Aratijo, W Jetz & C Rahbek
`SEE N&V P.461
`
`GENOMICS The Medicago genome
`provides insight into the evolution of
`rhizobial symbioses
`ND Youngetal.
`
`NEUROBIOLOGY Natural polymorphisms
`in C. elegans HECW-1 E3ligase affect
`pathogen avoidance behaviour
`HC Chang, J Paek & DH Kim
`
`VIROLOGY Adherensjunction protein
`nectin-4 is the epithelial receptor for
`measles virus
`MD Muhlebachetal.
`
`534 PARASITOLOGY Basigin is a receptor
`essential for erythrocyte invasion by
`Plasmodium falciparum
`C Crosnieretal.
`
`538
`
`543
`
`547
`
`552
`
`597
`
`561
`
`565
`
`570
`
`IMMUNOLOGY Responseto self antigen
`imprints regulatory memory in tissues
`M D Rosenblum et al.
`
`CELL BIOLOGY Excitation-induced
`ataxin-3 aggregation in neurons from
`patients with Machado-Joseph disease
`PKochetal.
`
`STEM CELLS Dopamine neurons derived
`from human EScells efficiently engraft
`in animal models of Parkinson's disease
`S Kriks etal.
`
`METABOLISM Cryptochromes
`mediate rhythmic repression of
`the glucocorticoid receptor
`KALamia etal. SEE N&V P.466
`
`BIOCHEMISTRY GleNAcylation of histone
`H2B facilitates its monoubiquitination
`R Fujiki et al.
`
`MOLECULAR BIOLOGY An equilibrium-
`dependent retroviral mRNA switch
`regulates translational recoding
`B Houck-Loomis etal.
`
`STRUCTURAL BIOLOGY Structures of
`the multidrug exporter AcrB reveal a
`proximal multisite drug-binding pocket
`R Nakashima, K Sakurai, S Yamasaki,
`K Nishino & A Yamaguchi
`BIOCHEMISTRY Intermediatesin the
`transformation of phosphonates
`to phosphate by bacteria
`SS Kamat, HJ Williams & F M Raushel
`
`GENOMICS
`
`Top model
`
`The genomeofbarrel clover, green
`
`manure and model legume. PAGE 520
`
`|
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`22/29 DECEMBER 2011 | VOL 480 | NATURE | 409
`
`NEW ONLINE
`459 Papers publishedthis weekat nature.com
`
`NEWS & VIEWS
`460 PLANETARY SCIENCE
`Theultimatefate of planets
`Discovery of a planetary system in orbit
`around an evolved star
`Eliza MR Kempton SEE LETTER P.496
`ECOLOGY
`Bleak future for amphibians
`Predicting the distribution of
`threats to amphibians
`Ross A Alford SEE LETTER P.516
`
`461
`
`MATERIALS SCIENCE
`
`Take charge
`
`Repackaging organic semiconductors
`to be moreflexible. PAGE 504
`
`ier
`
`ryeatt Rt ¢ a WYWAY
`
`a
`
`463 ATOMIC PHYSICS
`When ultracold is not cold enough
`How to cool quantum atomic gasesin
`optical lattices
`Gretchen K Campbell SEE LETTER P.500
`463 PSYCHOLOGY
`Who needs a leader?
`The dynamicsofjoint improvisation
`Sadaf Shadan
`
`465 CONDENSED-MATTER PHYSICS
`A fresh twist on shrinking materials
`Negative thermal expansionin
`scandium trifluoride
`J PaulAttfield
`
`466 PHYSIOLOGY
`On time metabolism
`Glucocorticoid signalling by the clock
`Joseph Bass SEE LETTER P.552
`468 EDITORS’ CHOICE
`The News & Viewshighlights of 2011
`
`

`

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`92/29 December 2011 / Vol 480 / Issue No. 7378
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`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`REVIEW
`
`
`
`
`doi:10.1038/nature10673
`
`Cancer immunotherapy comesof age
`
`Ira Mellman!, George Coukos? & Glenn Dranoff?
`
`Activating the immunesystem for therapeutic benefit in cancer has long been a goal in immunology and oncology. After
`decadesofdisappointment,the tide has finally changed due to the success of recent proof-of-concept clinical trials. Most
`notable has beenthe ability of the anti-CTLA4 antibody, ipilimumab, to achieve a significant increase in survival for
`patients with metastatic melanoma, for which conventional therapies havefailed. In the context of advances in the
`understanding of how tolerance, immunity and immunosuppression regulate antitumour immuneresponses together
`with the adventof targeted therapies, these successes suggest that active immunotherapy representsa path to obtain a
`durable and long-lasting response in cancerpatients.
`
`
`
`BOX|
`Established immune treatments
`
`
`
`T he passive transfer of anticancer monoclonal antibodies and
`
`donorT cells in the context of allogeneic bone marrow trans-
`plantationare effective treatments for a variety ofhaematological
`and solid malignancies'. Although not always thoughtofas ‘immuno-
`therapy’, the successofthese biotherapeutics probably reflects the ability
`of the donor cells or antibodies to induce an immediate immune
`reaction against
`the cancer, bypassing the requirement
`to activate
`endogenous immunity. These immune treatments have been well-
`established in oncology for several decades, and continued advances
`in antibody and T-cell engineering should further enhancetheir clinical
`impact in the years to come (Box1).
`In contrast to these passive immunotherapy strategies, the active
`stimulation ofspecific and durable antitumour immunity has proved
`elusive. In 1891, William Coley, a young New York surgeon, began
`intratumoral injections oflive or inactivated Streptococcus pyogenes
`and Serratia marcescens in an effort to reproduce the spontaneous
`remissions of sarcomas observed in rare-cancer patients who had
`developed erysipelas*. Given Elie Metchnikoff’'s contemporaneous work
`demonstrating the immunesystem’s ability to cause inflammation and
`destroy invading bacteria, ‘Coley’s toxins’ made sense by acting to
`stimulate antibacterial phagocytes that might kill bystander tumour
`cells. Some significant responses were recorded over the ensuing 40
`years, but successes were sporadic, difficult
`to reproduce and not
`obtainedin a scientifically rigorous fashion. Superficial bladder cancer
`was one notable exception, for which the intravesical injection oflive
`bacillus Calmette-Guerin after surgical resection was shownto prolong
`patient survival’. Otherthanthis particularclinical setting, the approach
`was never embraced by oncologists who continued to rely on surgery
`and, increasingly, oneffective new methods, such as radiation therapy
`and ultimately chemotherapy. Coley’s strategy was further discounted
`dueto the very real risks associated with the administration ofinfectious,
`orat least pyrogenic, agents to already weakened cancerpatients; thisis
`ironic given the trauma associated with the treatments that did come
`into common use. Thus began the history of cancer immunotherapy.
`Before continuing, however,it is useful to summarize what must happen
`to elicit a protective immuneresponseto cancer, and why overcoming
`these barriers has been so difficult.
`
`Nine monoclonal antibodies targeting six cancer-associated
`proteins (Her2/neu, EGFR, VEGF, CD20, CD52 and CD33) are
`approvedfor the treatment of solid and haematological
`malignancies. In addition to antagonizing oncogenic pathways,
`these biotherapeutics may act by opsonizing tumour cells and
`triggering their death or removal by antibody-dependent cellular
`cytotoxity or phagocytosis**. Ongoing investigations in murine
`models and patients raise the possibility that they may also
`stimulate adaptive immune responses in some settings®®.
`Recently, the successful conjugation of toxins to antibodies has
`been achieved, and these have induceda clinical response in
`patients who are refractory to the naked antibody®®. The
`concurrent administration of immunostimulatory cytokines such
`as IL-2 and GM-CSF may also enhancethe efficacy of antibody
`therapy.
`Allogeneic bone marrow transplantation and the infusion of
`donor lymphocytes can be a highly effective therapy for some
`leukaemias and lymphomas. The graft-versus-leukaemia effects
`involve the direct killing of tumour cells by donor lymphocytes,
`together with the subsequent induction of broader innate and
`adaptive reactions. On the basis of these clinical benefits, many
`groups are exploring the use of adoptive T-cell therapy in the
`autologous setting. Promising strategies include the use of
`lymphodepletion before T-cell infusion, and the engineering of
`new T-cell specificities with CARs?’.
`Other immune treatments that have received the FDA approval
`include recombinant cytokines, such as IL-2 (Proleukin), which is used
`for melanoma and renal cell cancer. Response rates are low (~15%)
`and the significant risk of serious systemic inflammation requires
`administration as an in-patient. Interferon-« is another agent that
`gained approval for ‘immunological cancers’(that is, melanoma or
`renal cell cancer). Although also associated with low response rates
`and high-dosetoxicity, a small subset of melanomapatients, who are
`also predisposed to autoimmunity, has been shown to exhibit an
`impressive survival response™. It has been, however,difficult to pre-
`Generating anticancer immunity is a multistep challenge
`identify these patients, which limits the use of the approach. Yet, when
`Based on our current understanding of the immune response, there
`seen, responsesare durable, suggesting they reflect active antitumour
`are three distinct steps that must be achieved, either spontaneously or
`immunity.
`therapeutically, to mounteffective antitumour immunity (Fig. 1). To
`
`
`
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`‘Genentech, 1 DNA Way, South San Francisco,California 94080, USA. “Ovarian Cancer Research Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
`*Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber CancerInstitute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
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`480 | NATURE | VOL 480 | 22/29 DECEMBER 2011
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`immunization
`Antigen
`
`processing
`
`
`Dendritic
`Antigen
`
`cells
`uptake
`responses.
`
`Tumour
`Cytotoxic
`
`antigen
`T call
`
`
`Dendritic cell
`maturation
`
`Sie a
`
`‘orevESE
`
`ectopically on the plasma membrane (for example, calreticulin) that
`promote their phagocytosis, possibly enabling the presentation oftumour
`antigens on major histocompatibility complex (MHC)classI andclass II
`molecules. Some forms of chemotherapy or targeted therapy may pro-
`mote a more immunogenic phenotype’.
`Next,
`in lymphoid organs, tumour-antigen-loaded dendritic cells
`must generate protective T-cell responses’. The precise type of T-cell
`response needed is unknown, but they certainly include the production
`of CD8* effector T cells with cytotoxic potential. Dendritic cells may
`also trigger antibody andnaturalkiller (NK) ornatural killer T (NKT)-
`cell responses, which may contribute to tumour immunity. The lymph
`node is a second potential site for therapeutic intervention, providing
`agents that may help guide the T-cell response. However,the dendritic
`cells are again key players because they must have been matured by a
`stimulatory adjuvant to have a chanceateliciting the desired T cells.
`Presentation of antigens by dendritic cells at the steady state (thatis,
`dendritic cells that have notreceived an immunogenic maturation signal)
`promotes tolerance by regulatory T cell (T,.g) production'’, which
`would oppose an antitumour response.
`
`22/29 DECEMBER 2011 / VOL 480 | NATURE | 481
`
`Figure 1 | Generation and regulation of antitumour immunity.
`BOX 2
`Understanding the events in generating and regulating antitumour immunity
`Mechanismsof immunesuppression
`suggestsatleast three sites for therapeutic intervention: promoting the antigen
`presentation functionsof dendritic cells, promoting the production of
`Tumours escape immuneattack by a variety of complementary
`protective T-cell responses and overcoming immunosuppressionin the tumour
`mechanisms of immunosuppression, many of which operate in
`bed. Antitumour immune responses must begin with the capture of tumour-
`associated antigens by dendritic cellls, either delivered exogenously or captured
`parallel. Among paracrine mediators, adenosine, prostaglandin E2,
`from dead or dying tumourcells. The dendritic cells process the captured
`TGF-f and VEGF-A exert multiple direct and indirect
`antigen for presentation or cross-presentation on MHCclass I] andclass |
`immunosuppressive activities. These mediators may function in the
`molecules, respectively, and migrate to draining lymph nodes. If capture and
`suppression of dendritic cells, indirectly inhibiting T-cell penetration
`presentation occurredin the presence ofan immunogenic maturation stimulus,
`into the tumour bed or directly suppressing effector T-cell activation
`dendritic cells willelicit anticancer effector T-cell responsesin the lymph node;
`while enhancing the function of T,., cells. For example, adenosine,
`if no such stimulus wasreceived, dendritic cells will instead induce tolerance
`which is released by tumour cells under hypoxia, contributes to the
`leading to T-cell deletion, anergy or the productionofT,,, cells. In the lymph
`suppression T-cell-activation and T,eg expansion. VEGF-A can also
`node,antigen presentationto T cellswill elicit a response depending onthe type
`of dendritic cell maturation stimulus received and on the interaction of T-cell
`suppress proper T-celldevelopmentand function: VEGF-A treatmentof
`co-stimulatory molecules with their surface receptors on dendritic cells. Thus,
`mouse splenocytes during T-cell stimulation was shown to induce IL-
`interaction of CD28 or OX40 with CD80/86 or OX40L will promotepotentially
`10 production fromTcells while suppressing IFN-y production®?.
`protective T-cell responses, while interaction of CTLA4 with CD80/86 or PD-1
`Tumour cells can also directly escape T-cell recognition by
`with PD-L1/PD-L2will suppress T-cell responses, and possibly promote T,.g
`downregulating MHC class| or by disabling other components of the
`formation. Antigen-educated T cells (along with B cells and NK cells) will exit
`antigen processing machinery. Shedding of soluble NKG2D ligands
`the lymph node and enterthe tumourbed, where a host of immunosuppressive
`such as MIC-A or MIC-B can severely compromisethe ability of effector
`defence mechanismscan be produced by tumours(orinfiltrating myeloid cells)
`T cells to function in the tumour microenvironment.In addition, tumour
`that oppose effector T-cell function. These include the upregulation of PD-L1/
`cells may upregulate surface ligands, which mediate T-cell anergy (or
`L2 onthe cancercell surface, release of PGE2, arginase and IDO (all T-cell
`exhaustion), including PD-L1 and other ligands to inhibitory T-cell
`suppressors), and the release of VEGF(triggered in part by intratumoral
`receptors. A variety of leukocyte subsets infiltrating tumours are also
`hypoxia), which inhibits T-cell diapedesis from the vasculature, and thus
`infiltration into the tumourbed.
`able to suppress T-cell function. In addition to T,eg cells (the
`accumulation of which in tumours correlates with poor prognostic
`outcome'*), other suppressive lymphocyte subsets have been
`initiate immunity, dendritic cells must sample antigens derived from the
`reported including IL-10 producing B cells and B regulatory cells, typell
`tumour, which canbe ingested in situ or delivered exogenouslyas part of
`NKTcells, NK cells and 76Tcells. Myeloid lineage cells also promote
`a therapeutic vaccine. These antigens might reflect one or moreof the
`immune suppression in tumours. Among these are mainly the poorly
`many mutatedproteins that are typical of cancer, the products of non-
`understood myeloid-derived suppressorcells (MDSC)!™. Their
`mutated genes that are preferentially expressed by cancercells (for
`characterization is ultimately based ontheir ability to suppress T and
`example, cancer-testis antigens), or differentiation antigens associated
`NK cell activation, probably through several mechanismsincluding
`with the cancer’stissue of origin, but against which thymic or peripheral
`nitric oxide, reactive oxidative species, arginase,IL-10 and TGF-f; there
`tolerance has not been completely established (for example, melanosome-
`are also reports that MDSCs mayspecifically induce the expansionof
`associated proteins in melanoma)**. Onantigen encounter, the dendritic
`Treg cells. Tumourstroma cells have an importantimmune modulatory
`cells would also haveto receive a suitable activation (‘maturation’) signal,
`role. The so-called cancer-associatedfibroblasts can promote the
`allowing them to differentiate extensively to promote immunity as
`recruitment and function of immunosuppressivecells through the
`opposed to tolerance including enhanced processing and presentation
`secretion of CCL2 and CXCL12.In addition, they can suppresseffector
`of tumour-antigen-derived peptides*’. Activation signals could be
`T-cells through secretion of TGF-f. Finally, myeloid-derived
`therapeutically supplied exogenously (for example, Toll-like receptor
`mesenchymal stem cells exert important immunosuppressive
`(TLR) ligands or agonist antibodies against activating receptors such as
`functions by blockingproliferation and function of T effectorcells.
`CD40) or endogenously: dying or necrotic tumourcells release factors
`Further study is needed to determine which of these mechanisms are
`(for example, high mobility group proteins or ATP) that are thought to
`most important in general, and which determine the immune status in
`result in the immunogenic maturation of dendritic cells. In addition,
`tumourcells seem to express resident endoplasmic reticulum proteins
`
`individual patients.
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`REVIEW
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`minimal therapeutic benefits. Recently, however, the co-administration
`Finally, cancer-specific T cells must enter the tumour bed to perform
`ofinterleukin (IL)-2 as an immunestimulantwith a short peptide derived
`their function at which point immunesuppression becomesa challenge
`from glycoprotein 100 (gp100), a melanocyte differentiation antigen,
`(Box 2). Tumours may (presumably by skewing dendritic cell matura-
`was shown, under someconditions, to augment tumour responses and
`tion) prevent immunization, trigger the ‘wrong’ immune response or
`enable the local accumulation or expansion of T,.g cells that would
`prolong progression-free survival compared with IL-2 alone in advanced
`oppose the activity of effector T cells. Indeed,infiltration of T,.. cells
`melanomapatients’. These findings indicate that increasing immune
`correlates with poor prognosisin a variety ofepithelial tumourtypes'""’.
`activation with peptide vaccines is a critical step for improving thera-
`Tumours may downregulate their expression of MHCclass I molecules
`peutic efficacy.
`or their expression of target tumour antigens and can also produce a
`Because the importance and function of dendritic cells in stimulating
`variety of surface molecules (for example, PD-L1 or PD-L2)that engage
`T-cell responses is now well known, current vaccine trials are designed
`receptors on the surfaces of activated T cells (PD-1), causing T-cell
`morerationally. One potentially promising approach involves the use of
`anergy or exhaustion'®’’. Expression of such suppressive ligands can
`peptides (~20-mer) that are somewhatlongerthan those that bind to MHC
`be associated with oncogenic mutations seen in many cancers (for
`class I molecules (10-12-mer). In the presence of a suitable dendritic-cell-
`example, PTEN loss)'*. Additionally, tumours can release immuno-
`activating adjuvant, these peptides are thought to be moreefficient at
`suppressive molecules, such as indoleamine 2,3-dioxygenase (IDO),