THE INTERNATIONAL WEEKLY JUURNAL OF SCIENCE
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`Genome & Co. v. Univ. of Chicago
`
`PG R201 9-00002
`
`The newsmakers of the year must
`
`UNIV. CHICAGO EX. 2036
`
`0 NhTURE.SBMlNATU
`221'29 Deter. =i'.-;:r 2011
`
`REBOOTING
`PHYSICS
`articlecouldtiestring
`PAIGE415
`
`[90111) to standard model
`
`CREAM OF
`THE CROP
`Editors’pickof2011’s
`PAGE453
`
`outstanding articles
`
`EVENTS
`DIRECTORY 2012
`Yourguidetoglobalscientific
`EIIIIIIPAGES8;NATUHEE‘JENTSWM
`
`events and courses
`
`0
`
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`lI>
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`

`

` CONTENTS
`
`22i29 December 2011 1' Vol 480 i Issue No 7378
`
`EDITORIAL
`414 Ten for 2011
`
`Capturing the characters of the year
`
`NEWS
`428 2011 in review-
`' From scandals to-fallout and all
`
`points between
`
`430 Images oftheyea'h '
`
`-
`-
`FEATURES
`_-
`_
`__
`43?-Natune's-10'_-
`Who were the people who made a
`mark on the past 12 months?
`
`'---*-.':-32011_ IN REVIEW -'
`
`I
`
`they-rear in sL'TGTTCE’
`
`355DAYS;
`
`COMMENT _
`44? The new history
`Philip Bail
`The major events of 201 1 were
`driven by odmplexity as well as
`social media and-globalization
`
`' Hm a. hauls
`4BR Editors’ choice
`A look back at some ofthe
`highlights from this year's
`News 8: Views -
`
`Cover and illustrations by Carl DeTorres
`
`:) naturecnm/ZOII
`
`THIS \VEEK
`
`I
`
`NEWS IN FOCUS
`
`I
`
`COMMENT
`
`EDITORIALS
`4i3 POLICY
`
`The morning after
`The US government was wrong to
`overrule recommendations on Plan B
`
`413
`
`ENVIRONMENT
`Defend the Amazon
`Brazi l’s attem pts to reform forest
`protection must be reworked
`
`WORLD 1VIE‘ILI
`
`415 Particle physics is at a turning point
`Gordon Kane
`
`The putative discovery of the Higgs
`boson is a boon for string theorists
`
`RESEARCH NICHLICNTS
`4H3 SELECTIONS FROM THE
`SCIENTIFIC LITERATURE
`Mercury's
`magnetosphere / Egg
`counts / Bacterial
`
`
`
`microtubules/ Why
`frogs make music / Lost
`Hoxgenes/Owningthe
`world / Neanderthals
`not upto sniff
`
`SEVEN OATS
`418 THE NEWS IN BRIEF
`Fukushima finally 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
`
`424 ANIMAL RESEARCH
`Report spells out
`tough criteria for
`NIH-funded chimp
`research
`
`closerto reality
`
`425 POLICY
`
`US integrity rules edge
`
`449 SCIENCE PUBLISHING
`The paper is not sacred
`Adam Marcus & ivan Oransky
`The rise in retractions this year argues
`forthe broadening of peer review
`
`OOOIIS 8: ARTS
`451 TECHNOLOGY
`Rise of the e-book
`CariZimmer
`
`452 FOOD SCIENCE
`
`With pipette and ladle on
`
`
`
`.
`
`I
`
`Harold McGee '
`453 O&A
`The snowflake designer
`Physicist Kenneth Libbrecht takes the
`study of snowflakes to extremes
`455 IN RETROSPECT
`0n the Six-Cornered Snowflake
`Philip Bali
`
`CORNESPONOENCE
`45? Leonardo da Vinci’s physics / Europe's
`threatened vultures / The first cells
`
`ORITIIAIIT
`45!] Lynn Margulis(1938—2011)
`JamesA Lake
`
`
`ELITIIRES
`5TB Tea with Jillian
`
`Brenda Cooper
`
`
`
`CAREERS
`
`575 AWARDS
`Conscientious counsellors
`
`Nature‘s 201 1 mentoring awards go
`Parisienne
`
`576 COLUMN
`
`Testing the waters
`Postdocs and industry do mix, say
`Christopher Tsang and Michael Fisher
`
`nature events
`
`Your guide to global scientific events
`and courses in 2012
`
`
`
`22!?9 DECEMBER 20“.
`
`VOL 480 I NATURE I 40?
`
`

`

`C UNTENTS
`
`2209 December 2011 J Vol 480 f Issue No 7378
`
`RESEARCH
`
`REVIEWS
`4?] ORGANIC CHEMISTRY Rethinking
`amide bond synthesis
`1/ I? Pattabiraman & J W Bode
`
`4Bl] CANCER Cancerimmunotherapy
`comes of age
`IMelIrnan, G Coukos (5 G Dranoff
`
`ARTICLE
`
`490 CENOMICS DNA-bindingfactors
`shape the mouse methylome at
`distal regulatory regions
`MBStadIeret al.
`
`lETTEBS
`496 ASTRONOMY A compact system of small
`planets around a former red-giant star
`5 Charpinet et al. SEE Mav P460
`
`500
`
`504
`
`509
`
`513
`
`516
`
`520
`
`525
`
`53C
`
`PHYSICS Orbital excitation blockade and
`algorithmic cooling in quantum gases
`W8 Bakret al. SEE Hev R453
`
`MATERIALS SCIENCE Tuning charge
`transport in solution-sheared organic
`semiconductors using lattice strain
`GGirietal.
`
`CLIMATE SCIENCE Forcing of wet phases
`in southeast Africa over the past
`17,000 years
`E Schefufli, H Kuhi'mann, G Moilenhauer,
`M Prange :5 J Pétzoid
`
`PALAEONTOLOCY Lowland—upland
`migration of sauropod dinosaurs during
`the Late Jurassic epoch
`H C Fricke, J Hencecroth d: M E Hoemer
`
`ECOLOGY Additive threats from
`pathogens. climate and land-use
`change for global amphibian diversity
`C Hot, M BArarijo, WJetz :5 C Rahbek
`SEE nev H461
`
`CENOM ICS The Medicago genome
`provides insight into the evoiution of
`rhizobial symbioses
`N D Young et at
`
`NEUROBIOLOCY Natural polymorphisms
`in C. el'egans HECW-l E3 ligase affect
`pathogen avoidance behaviour
`H C Chang J Peek & D H Kim
`
`YIBOLOCY Adherens junction protein
`nectin-4 is the epithelial receptor for
`measles virus
`M D Miihleoacn et al.
`
`534
`
`538
`
`543
`
`54?
`
`552
`
`557
`
`551
`
`535
`
`57C
`
`PARASITOLOCY Basigin is a receptor
`essential for erythrocyte invasion by
`Piasmodiurn faiciparum
`C Crosnier et al.
`
`IMMUNOLOGY Response to selfantigen
`imprints regulatory memory in tissues
`M 0 Rosenblum et al.
`
`CELL BIOLOGY Excitation-induced
`ataxin-3 aggregation in neurons from
`patients with Machado—Joseph disease
`PKoch etal.
`
`STEM CELLS Dopamine neurons derived
`from human ES cells efficiently engratt
`in animal models of Parkinson's disease
`SKriks etal.
`
`METABOLISM Cryptochromes
`mediate rhythmic repression of
`the glucocorticoid receptor
`K A Lamia et al. sat nav R466
`
`BIOCHEMISTRY GlcNAcylation of histone
`H23 facilitates its monoubiquitination
`RFujr'ki et al.
`
`MOLECULAR BIOLOGY An equilibrium-
`dependent retroviral mRNA switch
`regulates translational recoding
`8 Houck-Loomis et al.
`
`STRUCTURAL BIOLOGY Structures of
`the multidrug exporter Ach reveal a
`proximal multisite drug-binding pocket
`R Nakashima, K Sakurai, S Yamasaki,
`K Nishr'no it A Yamaguchi
`BIOCHEMISTRY Intermediates in the
`transformation of phosphonates
`to phosphate by bacteria
`88 Kamat H J Williams S F M Raushel
`
`CENOMICS
`
`Top model
`
`The genome of barrel clover, green
`manure and model legume. m: 520
`
`
`
`22r‘29 DECEMBER 2011 i VOL. 430 | NATURE i 409
`
`HEW OHLINE
`459 Papers published this week at naturecom
`
`HE'NS NEWS
`430 PLANETARY SCIENCE
`The ultimate fate of planets
`Discovery of a planetary system in orbit
`around an evolved star
`Eliza M R Kempton SEE LETTER R496
`ECOLOGY
`
`48]
`
`Bleakfuturetor amphibians
`Predicting the distribution of
`threats to amphibians
`RossAAlford SEE LETTER R516
`
`MATERIALS SCIENCE
`
`Take charge
`
`Repackaging organic semiconductors
`to be more flexible. PACEEM
`
`r
`
`-
`
`ufl‘ i; .
`
`.i.
`
`.1
`
`-.
`
`.
`
`'1"; 5 I“ “‘1‘”ij
`
`463 ATOMIC PHYSICS
`When ultracold is not cold enough
`How to cool q uantu in atomic gases in
`optical lattices
`Gretchen K Campbeii SEE LETTER P.500
`PSYCHOLOGY
`Who needs a leader?
`The dynamics of joint improvisation
`Sada! Shadan
`
`453
`
`465
`
`CONDENSED-MATTER PHYSICS
`A fresh twist on shrinking materials
`Negative thermal expansion in
`scandium trifluoride
`J PauiAtttieId
`
`465
`
`PHYSIOLOGY
`On time metabolism
`
`Glucocorticoid signalling by the clock
`Joseph Bass SEE LEITER P.552
`EDITUHS' CHOICE
`
`483
`
`The News 8: Views highlights of 2011
`
`

`

`nature
`
`22129 December 2011 I V01480 1 Issue No. 7378
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`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`REVIEW
`
`
`
`
`doi:10.103§_/na_ture106?3
`
`Cancer immunotherapy comes of age
`
`Ira Mellman', George Goukos2 8r Glenn Dranoff3
`
`Activating the immune system for therapeutic benefit in cancer has long been a goal in immunology and oncology. After
`decades of disappointment, the tide has finally changed due to the success of recent proof-of—concept clinical trials. Most
`notable has been the ability of the anti-CTLA4 antibody, ipiliniumab, to achieve a significant increase in survival for
`patients with metastatic melanoma, for which conventional therapies have failed. In the context of advances in the
`understanding of how tolerance, immunity and immunosuppression regulate antitumour immune responses together
`with the advent of targeted therapies, these successes suggest that active immunotherapy represents a path to obtain a
`durable and long— lasting response in cancer patients.
`
`T he passive transfer of anticancer monoclonal antibodies and
`
`donor T cells in the context of allogeneic bone marrow trans—
`plantation are effective treatments for a variety of haematological
`and solid malignancies‘. Although not always thought of as ‘immuno—
`therapy’, the success of these biotherapeutics probably reflects the ability
`of the donor cells or antibodies to induce an immediate immune
`
`to activate
`the cancer, bypassing the requirement
`reaction against
`endogenous immunity. These immune treatments have been well—
`established in oncology for several decades, and continued advances
`in antibody and T-ccll engineering should further enhance their clinical
`impact in the years to come (Box 1).
`In contrast to these passive immunotherapy strategies, the active
`stimulation of specific and durable antitumour immunity has proved
`elusive. In 1891, William Coley, a young New York surgeon, began
`intratumoral injections of live 01' inactivated Streptococcus pyogerres
`and Serratia marcescens in an effort to reproduce the spontaneous
`remissions of sarcomas observed in rare-cancer patients who had
`developed erysipelasz. Given Elie Mctchnikoff’s contemporaneous work
`demonstrating the immune system’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
`obtained in a scientifically rigorous fashion. Superficial bladder cancer
`was one notable exception, for which the intravesical injection of live
`bacillus Calmette—Guerin after surgical resection was shown to prolong
`patient survival? Other than this particular clinical setting. the approach
`was never embraced by oncologists who continued to rely on surgery
`and. increasingly, on effective new methods, such as radiation therapy
`and ultimately chemotherapy. Coley‘s strategy was further discounted
`due to the very real risks associated with the administration of infectious,
`or at least pyrogenic, agents to already weakened cancer patients; this is
`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 immune response to 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
`approved for 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 phagocytosisg‘. 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 induced a clinical response in
`patients who are refractory to the naked antibody)“. The
`concurrent administration of immunostimulatory cytokines such
`as lL-2 and GM—CSF may also enhance the 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. 0n the basis of these clinical benefits. many
`groups are exploring the use of adoptive T—ceil 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 recombinantcytokines. such as lL—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-ct 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—dose toxicity. 3 Small subset of melanoma patients. who are
`also predisposed to autoimmunity. has been shown to exhibit an
`impressive survival response”. It has been. however,difiicult 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. responses are durable. suggesting they reflect active antitumour
`are three distinct steps that must be achieved, either spontaneously or
`immunity.
`therapeutically, to mount effective antitumour immunity (Fig. I). To
`
`
`
`
`nor 1
`
`Established immune treatments
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`
`
`
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`"Genentech, 1 DNA Way. South San Francisco. California 94080, USA. 2Dvmian Cancer Research Center. University of Pennsylvania School of Medicine. Philadelphia. Pennsylvania 19104. USA.
`3Department of Medical Oncology and Cancer Vaccine Center. Dana-Farber Cancer Institute. Brigham and Women's Hospital and Harvard Medical School. Boston. Massachusetts 02115.U3A.
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`480 - NATURE l
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`\I'UI. 480 | 22l29 DECEMBER 2EIII
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`Immunization
`Mligen
`processing
`
`Ant-gen
`
`
`
`uptake
`
`responses
`
`Tfitour
`Cytotoxic
`
`maturation
`of
`
`Murine cell *anthen
`T cell
`*
`50
`
`\mspnnses
`b.
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`Regulatory T-cell
`
`
`
`killing
`
`Figure 1 [Generation and regulation of antitumour immunity.
`Understanding the events in generating and regulating antitumour immunity
`suggests at least three sites for therapeutic intervention: promoting the antigen
`presentation functions of dendritic cells, promoting the production of
`protective T-cell responses and overcoming immunosuppression in the tumour
`bed. Antitumour immune responses must begin with the capture of tumour—
`associated antigens by dendritic cellls, either delivered exogenously or captured
`from dead or dying tumour cells. The dendritic cells process the captured
`antigen for presentation or cross-presentation on MHC class II and class I
`molecules, respectively. and migrate to draining lymph nodes. If capture and
`presentation occurred in the presence of an immunogenic maturation stimulus.
`dendritic cells will elicit anticancer effector T -cell responses in the lymph mode:
`if no such stimulus was received. dendritic cells will instead induce tolerance
`leading to T—cell deletion. anergy or the production of TEE cells. In the lymph
`node. antigen presentation to T cells will elicit a response depending on the type
`of dendritic cell maturation stimulus received and on the interaction of T-cell
`ctr-stimulatory molecules with their surface receptors on dendritic cells. Thus,
`interaction of CD28 or 0X40 with CDSUIBS or OX4OL will promote potentially
`protective T-cell responses, while interaction of CTLA4 with CDSOi'Sfi or PD—l
`with PD—LHPD-LZ will suppress T—cell responses. and possibly promote Tms
`formation. Antigen—educated T cells (along with B cells and NK cells) will exit
`the lymph node and enter the tumour bed, where a host of immunosuppressive
`defence mechanisms can be produced by tumours (or infiltrating myeloid cells)
`that oppose effector T—cell function. These include the upregulation of F'D—LJar
`L2 on the cancer cell surface. release of PGE2. arginase and IDO (all T—cel]
`suppressors), and the release of VEGF (triggered in part by intratumoral
`hypoxia). which inhibits T-cell diapedesis from the vasculature. and thus
`infiltration into the tumour bed.
`
`initiate immunity. dendritic cells must sample antigens derived from the
`tumour. which can be ingested in situ or delivered exogenously as part of
`a therapeutic vaccine. These antigens might reflect one or more of the
`many mutated proteins that are typical of cancer, the products of non—
`mutated genes that are preferentially expressed by cancer cells (for
`example, cancer—testis antigens), or differentiation antigens associated
`with the cancer’s tissue of origin, but against which thymic or peripheral
`tolerance has not been completely established (for example, melanosome—
`associated proteins in melanoma)”. On antigen encounter, the dendritic
`cells would also have to receive a suitable activation (‘maturation‘l signal,
`allowing them to differentiate extensively to promote immunity as
`Opposed to tolerance including enhanced processing and presentation
`of tumour—antigen-derived peptides”. Activation signals could be
`therapeutically supplied exogenously (for example, Toll—like receptor
`(TLR) ligands or agonist antibodies against activating receptors such as
`CD40) or endogenously: dying or necrotic tumour cells release factors
`(for example. high mobility group proteins or ATP) that are thought to
`result in the immunogenic maturation of dendritic cells. In addition,
`tumour cells seem to express resident endoplasmic reticulum proteins
`
`War-
`
`ectopically on the plasma membrane (for example, calreticulin) that
`promote their phagocytosis. possibly enabling the presentation of tumour
`antigens on major histocompatibility complex (MHC) class 1 and class II
`molecules. Some forms of chemotherapy or targeted therapy may pro-
`mote a more immuuogenic 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 CDS+ effector T cells with cytotoxic potential. Dendritic cells may
`also trigger antibody and natural killer (NK) or natural 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 chance at eliciting the desired T cells.
`Presentation of antigens by dendritic cells at the steady state (that is.
`dendritic cells that have not received an immunogenic maturation signal)
`promotes tolerance by regulatory T cell (TR?) production'""”, which
`would oppose an antitumour response.
`
`not 2
`
`
`
`Mechanisms of immune suppression
`Tumours escape immune attack by a variety of complementary
`mechanisms of immunosuppression. many of which operate in
`parallel. Among paracr‘ine mediators. adenosine, prostaglandin E2.
`TGF-[i and VEGF-A exert multiple direct and indirect
`immunosuppressive activities. These mediators may function in the
`suppression of dendritic cells, indirectly inhibiting T—cell penetration
`into the tumour bed or directly su ppressing effector T—cell activation
`while enhancingthe function of Treg cells. For example, adenosine,
`which is released by tumour cells under hypoxia. contributes to the
`suppression T-cell—activation and T...B expansion. VEGF—A can also
`so ppress properTcel Idevelopment and function : VEGF—Atreatment of
`mouse splenocytes during T-cell stimulation was shown to induce lL—
`10 production from T cells while suppressing IFN—y productiong".
`Tumour cells can also directly escape T—cell recognition by
`downregulating MHC class I or by disabling other components of the
`antigen processing machinery. Shedding of soluble NKGZD ligands
`such as M IC-A or M [08 can severely compromise the ability of effector
`Tcellstofunction inthetumourmicroenvironment. ln addition,tumour
`cells may upregulate surface ligands, which mediate T—cell anergy (or
`exhaustion). including PD-Ll and other ligands to inhibitory T-cell
`receptors. A variety of leukocyte subsets infiltrating tumours are also
`able to suppress T-cell function. ln addition to 1193 cells (the
`accumulation of which in tumours correlates with poor prognostic
`outcome“). other suppressive lymphocyte subsets have been
`reported includinglL—lO producingB cells and B regulatory cells.type ll
`NKT cells. NK cells and 75 T cells. Myelold lineage ceils also promote
`immune suppression in tumours. Among these are mainly the poorly
`understood myeloid—derived suppressor cells (MDSC)1°°. Their
`characterization is ultimately based on their ability to suppress T and
`NK cell activation. probably through several mechanisms including
`nitric oxide. reactive oxidative species, argi nase. lL—lO and TGF—[i; there
`are also reports that MDSCs may specifically induce the expansion of
`THEE cells.Tumourstroma cells have an importantirnmune modulatory
`role. The so-called cancer—associated fibroblasts can promote the
`recruitment arid fu nction of immu nosu ppreSSive cells through the
`secretion of CCL2 and CXCL 1 2. In addition. they can suppress effector
`T-cells through secretion of TGF-B. Finally. myeloid—derived
`mesenchymal stem cells exert important immunosuppressive
`functions by blocking proliferation and function of T effector cells.
`Further study is needed to determine which of these mechanisms are
`most important in general, and which determinethe immune status in
`individual patients.
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`Finally, cancer-specific T cells must enter the tumour bed to perform
`their function at which point immune suppression becomes a challenge
`(Box 2). Tumours may (presumably by skewing dendritic cell matura—
`tion) prevent immunization, trigger the ‘wrong‘ immune response or
`enable the local accumulation or expansion of Tree. cells that would
`oppose the activity of effector T cells. Indeed, infiltration of True cells
`correlates with poor prognosis in a variety of epithelial tumour types'“ 5.
`Tumours may downregulate their expression of MHC class I molecules
`or their expression of target tumour antigens and can also produce a
`variety ofsurface molecules (for example, PD-Ll or PD-LZ) that engage
`receptors on the surfaces of activated T cells (PD-l). causing T-cell
`anergy or exhaustionw'”. Expression of such suppressive ligands can
`be associated with oncogenic mutations seen in many cancers (for
`example, PTEN loss)”. Additionally, tumours can release immuno-
`suppressive molecules, such as indoleamine 2,3—dioxygenase (IDO),
`which consumes tryptophan and limits T—cell functionw'z". Myeloid—
`derived suppressor cells can also be recruited into the tumour, and release
`additional T-cell suppressors, such as arginase and nitrous oxide
`synthase“. Hypoxia in the tumour microenvironment may promote the
`generation of adenosine, which inhibits efi'ector T—cell function in a
`similar