Mucosal immunology
`
`FOCUS
`
`Ris vaaove wD
`
`june 2008 volume8 no. 6
`www.nature.com/reviews
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`_ Collaborate
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`[Genome&Go.v. Univ. ofChicago
`m™PGR2019-00002
`UNIV. CHICAGO EX. 2008
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`PROPERTY OF THE
`NATIONAL
`=| IBRARY OF
`
`[NATIONALY
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`,
`we
`,
`penncaceleeelacie eeas
`
`rex rele
`
`Maintaining the inflammation—
`peare
`
`

`

`
`
`Dendritic-celltolerance versusimmunity p435
`
`CONTENTS
`
`©
`
`REVIEWS
`Epithelial-cell recognition of commensal
`bacteria and maintenanceof immune
`homeostasis in the gut
`David Artis
`It was thought thatintestinal epithelial cells
`functionedsolely as a barrier to the external
`environment, butas described here, these cells are
`now knownto have anintegralrole in facilitating and
`controlling crosstalk between commensal bacteria
`ancl the immune system.
`The regulation of IgA class switching
`Andrea Cerutti
`IgA is the most abundant antibody class andprovides a
`first line of defence at mucosalsurfaces. Class switching
`tolgA occurs throughboth T-cell-dependent and T-cell-
`andrecentstudiesreveal a role
`independent pathways,
`onses.
`for commensalbacteriain intestinal IgA resp
`Dendritic cells in intestinal immune regulation
`Janine L. Coombes and Fiona Powrie
`A delicate balance betweentolerance to commensal
`bacteria and immunity to pathogens occurs In the
`intestine. Intestinal dendritic cells have a central
`as described
`role in maintainingthis balance and,
`here, someof the molecular pathways involvedhave
`recently been resolved.
`
`FEATURED
`ARTICLE
`
`_ Setting the stage: host invasion by HIV
`© | Florian Hladik and M.Juliana McElrath
`Infection by HIV requires the virus to breach the
`mucosalbarrier to gain access to the immunecells
`that it infects. But what are the immediate events that
`follow HIV exposure at genital mucosal sites and what
`are the key cells thatfacilitate HIV invasion?
`
`The genetics and immunopathogenesisof
`inflammatory boweldisease
`Judy H. Cho
`Great progress has been made recently in the
`identification of genes or genetic loci that are associated
`with inflammatory boweldiseases. This knowledgeis
`now providing insight into the pathogenesis of these
`diseases, highlightingroles for genes involvedin
`bacterial sensing andcytokine signalling.
`
`_ Inhibitory B7-family molecules in the tumour
`microenvironment
`Weiping Zou and Lieping Chen
`This Review describes how the expression of inhibitory
`members of the B7 family, particularly B7-H1 and B7-H4,
`by cancercells, stromalcells and haematopoieticcells
`inthe tumour microenvironment is regulated and acts
`to inhibit -eell immunity, as well as the therapeutic
`implications.
`
`PowerPoint figures
`Links to further information
`On the web www.nature,com/reviews/immunol
`
`Figures can be downloadedas a PowerPointfile for
`Thefull text of articles includes:
`usein presentations and for teaching,
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`* Author biographies
`Advance online publication
`E-alert table of contents
`« Links to glossary terms
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`weew.nature.com/reviews/immunal
`More articleslike this for further reading.
`How regulatory T cells work
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`Each Review concludes with a ‘Morearticles like
`Dario A.A, Vignali, Lauren W, Collison and Creq J. Workman
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`this’ box containinglinks to related content on NPG.
`Unravelling the association of partial Fcell immunodeficiency
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`N
`NATUREREVIEWS| IMMUNOLOGY
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`This material was copied
`at the NLM and may be
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`VOLUME 8 | JUNE 2008
`
`

`

`FOCUS ON
`MUCOSAL
`IMMUNOLOGY
`This issue features a focus on
`mucosal immunology — see the
`articles markedwith the above
`logo. Thesearticles can also be
`foundonline, alongwith articles
`on mucosal immunology from our
`Past issues and from other Nature
`Publishing Groupjournals at:
`http://www.nature.com/nri/
`
`focus/mucosal
`
`How HIV invades p447
`
`nature
`REVIEWS
`
`
`CONTENTS
`
`FROM THE EDITORS
`An editorial commentary andintroductionto this month's issue
`RESEARCH HIGHLIGHTS
`Selected highlights from the recent research literature
`
`PERSPECTIVES
`OPINION
`
`Immunomodulatory mast cells: negative, as well as positive,
`regulatorsof immunity
`StephenJ. Galli, Michele Grimbaldeston andMindyTsai
`In this Opinionartic le, StephenGalli andcolleagues discuss the
`as well as positive,
`recent evidence that mast cells can have negative,
`immunomodulatory func tions, and suggest that mast ¢ ells might have
`phasesof an immuneresponse.
`distinct rolesat different
`T-cell quality in memory and protection: implications for
`vaccine design (Corrigendum)
`Robert A. Seder, Patric ia A. Darrah and Mario Roederer
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`4H?
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`NATURE REVIEWS|[IMMUNOLOGY
`This aah tt <-3i5e
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`FROM THE EDITORS
`
`atch out gastroenterologists! Many immunologists are
`now turning their attention to the study of immune
`responses at mucosal sites. Mucosal immunologyis
`attractive for several reasons. Mucosal surfaces comprise
`the body’sfirst line of defence against numerous pathogenic organisms.
`And understanding how the mucosal immunesystem is typically able to
`distinguish pathogens from the commensal microflora and innocuousfood
`antigens and respond appropriately to each challenge is a fascinating
`conundrum. When the mucosal immunesystem fails to discriminate between
`good and bad, the consequences — such as inflammatory boweldisease and
`food allergy — can be devastating. Exciting research is now providing clues
`to the inner workings of the mucosal immune system, and the harnessing
`of its unusual features to prevent or treat disease shows promisefor the
`developmentof new mucosal vaccines, adjuvants and immunotherapeutics.
`Five articles in this issue review the latest developmentsin thefield
`of mucosal immunology. David Artis assigns renewed importance to the
`ons ofintestinal epithelial cells. Janine Coombes and Fiona Powrie
`functi
`dissect the role of dendritic cellsin intestinal immune regulation. Andrea
`Cerutti details the regulation of IgA, the body's most abundant antibody
`class. Judy Cho draws onlessonslearnt from genome studies to understand
`inflam matory bowel diseases, and Florian Hladik and Juliana McElrath
`cover the invasion of genital mucosal sites by HIV.
`The importanceofthis fast-growingfield is also illustrated by the recent
`partnership between the Society for Mucosal Immunology and the Nature
`Publishing Group in the productionof the new journal Mucosal Immunology.
`e Federation of Clinical Immunology Societies (FOCIS) and
`Finally, we thank th
`BeckmanCoulter for supporting this Focusissue.
`
`Nature
`
`@®Mucosal inmunolayy
`
`REVIEWS
`
`» COVER: ‘Ry
`llections on mucosal immunology’.
`by Si
`I ‘s f he Bradbrook. € Jriginal image courtesy of
`Mid Artis (dartis@vet.upenn.edu).
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`
`REVIEWS
`
`Inhibitory B7-family molecules in the
`tumour microenvironment
`
`Weiping Zou* and Lieping Chen‘
`Abstract | The B7 family consists of activating andinhibitory co-stimulatory molecules that
`positively and negatively regulate immuneresponses. Recentstudies have shown that human
`and rodentcancercells, and stromal cells and immunecells in the cancer microenvironment
`upregulate expressionof inhibitory B7 molecules andthat these contribute to tumour immune
`evasion.In this Review, we focusontheroles of these B7 molecules in the dynamic interactions
`between tumoursandthe host immunesystem,including their expression, regulation and
`functionin the tumour microenvironment. Wealso discuss novel therapeutic strategies that
`target these inhibitory B7 molecules andtheir signalling pathways to treat human cancer.
`
`|
`
`Tumour-associated antigens
`We) Fees Mal are
`Anressed Oy tumour cell
`These bolone lo
`three marr
`
` Halon anilipens, WHICH
`Isc-exnressed by non
`int Cells; mutated or
` Ind Cancer LEShs
`
`
`Hole placenta
`
`Myeloid-derived suppressor
`cells
`A populaticn ¢ Peels (hal
`COMPRMSeCS Mature are
`Himaluire myeloid cells They
`wee panded andor activated
`CUP an iiternenalory
`TUNG FeSporse: Through
`
`er
`
`retoed comoaner
`\
`
`Is, they
`
`* Department of Surgery,
`University of Michigan, Ann
`Arbor, Michigan 48109, USA
`‘Departments of Dermatology
`and Oncology. Jolins Hopkins
`University School of Medicine,
`Baltimore, Maryland 21241,
`USA,
`e-mails: wzou@med, umich
`edu, Ichen4? @jhmi_edu
`dor de Aerie 426
`
`Thespecific function of an individual’s immunesystem
`in different physiological and pathological settings is
`regulated by the actions of opposing factors or sys-
`tems. Commonexamples ofthis are the polarization of
`T helper (T,,) cells into T) 1-cell and T,,2-cell subsets
`with opposing functions, and the balance betweeneffec-
`tor T-cell activation and regulatory T-cell activation. At
`the molecularlevel, co-stimulatory membersofthe B7
`family can haveboth inhibitory and stimulatoryeffects
`on T-cell activation.
`An imbalance in immuneregulation profoundly
`affects tumour-specific T-cell immunity in the cancer
`microenvironment andcan reshape tumourprogression,
`metastasis and immunotherapyin patients with cancer’, It
`is well knownthat thelack of naturally induced immunity
`specific for turnour-associated antigens (TAAs)is not simply
`a passive process wherebyadaptive immunityis shielded
`fromdetecting TAAs! °, [thas beenclearly shownthat the
`tumourmicroenvironmentis comprisedofdysfunctional
`immune cells that are reprogrammedbyactive tumour-
`mediated processes to evade tumour-specific immunityin
`a highly effective manner. Three important mediators of
`this evasion of tumour immunitythat have been identi-
`fied in the tumour microenvironmentare: dysfunctional
`antigen-presentingcells (APCs), including dendritic cells
`0
`(DCs), macrophages!"
`and mycloid-derived suppressor
`cells!’ ;epulatory F(T, cells"; and highlevels ofexpres-
`sion ofinhibitory B7 molecules by APCs, stromalcells and
`tumour cells!”. Thefirst two mediators have been spe-
`cifically reviewedin theliterature elsewhere’ WEE Th this
`Review, we focus on inhibitory B7 molecules, and detail
`their expression, regulation, function and therapeutic
`relevance in the tumour microenvironment.
`
`Inhibitory B7 molecules
`T-cell activation andtolerance are not chance occur-
`rences. Many molecules form an orchestrated system to
`regulate theinteractions between APCs andTcells. This
`interactionis explained bythe two signal model, whereby
`signal oneis providedtothe T-cell receptorofT cells by
`the presentationofspecific antigens on MHC molecules
`expressed by APCs, andsignal two is provided bythe B7
`family andother co-stimulatory molecules that APCs
`use to direct and/orfine-tune T-cell responses (HG.
`1).
`‘Thegrowing B7 family now comprises seven members,
`which are CD80(also knownas B7.1), CD86(also known
`as B7.2), B7-DC (also known as PD-L2 or CD273),
`B7-H1 (also known as PD-L1 or CD274), B7-H2 (also
`known as ICOSL), B7-H3 (also known as CD276) and
`B7-H4(also knownas B7S1 or B7x)'"
`“. Compelling
`evidenceindicates that B7 molecules not only provide
`crucial positivesignals to stimulate andsupport ‘T-cell
`activation, but canalso offer negative signals that control
`andsuppress T-cell responses! '*, Thesenegativesignals
`are largely provided by the newlyidentified B7-family
`members B7-H1 and B7-H4.
`
`CD80/CD86-CTLA4, CD80 and CD86control T-cell
`activation by binding to and signalling through two
`receptors, CD28 andcytotoxic Tlymphocyte antigen 4
`(CTLAA), that are expressed by T cells (FG 1), CD80
`and CD86arenotclassically consideredas inhibitory
`B7 molecules. However, on ‘T-cell activation, the expres-
`sion oftheir inhibitory receptor, CTLA4, is induced
`on T cells, and engagement of CTLA4 by CD80 and
`CD86can limit and decrease T-cell activation. The
`role of CTLA4 in controlling ‘T-cell activation andits
`
`NATURE REVIEWS | IMMUNOLOGY
`
`This material was copied
`atthe NLM and may be
`
`VOLUME 8 | JUNE 2008 | 467
`
`

`

`REVIEWS
`
`T cell
`
`co28
`
`cpss Ceo ———¥
`
`of=D crim
`
`TCR
`
`SS ORE) PD
`BHI (ao =~» ewe) cv20
`IcOs
`
`\gV-like domain
`
`\gC-like domain
`
`Figure 1| The B7 family and antigen presentation to
`T cells. Antigen-presenting cells (APCs) or APC-like cells
`present a specific antigen on MHCmolecules to the T-cell
`receptor (TCR) of T cells. Members of the B7 family and
`other co-stimulatory molecules are usedto direct and/or
`fine-tuneT-cell responses. The newly identified B7-H1
`and B7-H4 molecules provide negative signals that
`control andsuppress T-cell responses, Human tumour
`cells and tumour-associated APCs expresslimitedlevels
`of the stimulatory B7-family members CD80 and CD86,
`and highlevels of the inhibitory B7-family members
`B7-H1 and B7-H4.This imbalance between the expression
`of stimulatory andinhibitory B7 molecules might
`contribute to tumour immune evasion in the tumour
`
`microenvironment. CTLA4; cytotoxic T-lymphocyte
`antigen 4; COS, inducible Fcell co-stimulator; PD-1,
`programmed cell death1.
`
`therapeutic relevance have been reviewed elsewhere”
`andare not discussed in detail here. CTLA4-specific
`antibodies have recently enteredclinicaltrials for the
`treatment of various human cancers",
`
`B7-H1. B7-H1 was first cloned on the basis of its DNA
`sequence homology to other B7 molecules belonging
`to the immunoglobulin superfamily”. Programmed
`cell death 1 (PD-1; also known as CD279) has been
`subsequently identified as a counter-receptorfor B7-H1
`(REF 21) (HG.
`1), and B7-H1 is therefore also known as
`PD-L1 to emphasize this receptor-ligandinteraction”.
`However, experimental evidence indicates that addi-
`tional counter-receptor(s) other than PD-1 can mediate
`the functions of B7-H1. In the absence of PD-1 or if
`binding to PD-1 is blocked, B7-H1 can have a stimula-
`tory effect on T-cell immunity!" ", Moreover, CD80
`is an additional counter-receptor for B7-H1 for the
`inhibition of T-cell responses”. ‘To make thesituation
`more complicated, B7-H1 canalso functionas a receptor
`to transmit signals into T cells’ and tumour cells”. In
`summary, B7-H1 can act as bothligand andreceptor to
`execute immunoregulatory functions.
`
`Regulatory T (T,nop! Cells
`A T-cell population that can
`lunctionally Suppress an
`Immune response by
`Willuencre tie
`
`of another cell type
`Several phenotypically
`distinct reeulatary Peel
`populations exist The classi
`repulatory T cells are
`CD4°CB25"FOXPS*
`Known as 7,
`cells
`
`T cells
`
`Two-signal model
`The Concept that both the
`MHC-peptide complex
`(Signal 1) and co-stimulatory
`sipnals delivered by BY amily
`molecules expressed by
`
`INMIPEN-preser
`cells
`{signal 2) are required tor Pcell
`activation, The absence of
`Senal? results im the mducnon
`ot TPeell anergy or deletion
`
`Cytotoxic TFlymphocyte-
`antigen 4
` 1ement by
`(CTLAA), Aller enp;
`CD80 or CD86 on antigen
`presenting cells, CTLA4
`sleinalling inactivated T cells
`induces cell cycle arrest,
`decreases CyLOKING Production
`and inhibits Teell responses
`Co4'€D25'
`T,
`cells
`constitutively express CTLAA
`
`B7-H4, B7-H4 was alsoidentified by DNA sequence
`homologyto other B7 molecules* “. B7-H4 remains an
`orphanligand,althoughevidence indicates that a recep-
`tor can be induced and couldfunction on T cells**3""!,
`The currently knownfunctions of B7-H4are exclusively
`inhibitory andtheeffect of B7-H4 might be mediated
`by a single receptor, B- and ‘T-lymphocyte attenuator
`(BTLA) wasinitially proposed to be the receptor for
`B7-H4 (REF %2), but recent studies showthat this is not
`the case and that herpes virus entry mediatoris the
`ligand for BTLA® ©.
`
`Expression pattern
`CD80 and CD86have arestricted expression pattern,
`being expressed mainly by professional APCs and
`haematopoietic cells, but rarely by stromalcells and
`non-haematopoietic cancercells'™*. By contrast,mRNA
`encoding B7-H1 and B7-H4is foundin almostall tissues
`and most stromal and haematopoietic cells. This distri-
`butionpattern indicates uniquefunctions for these mol-
`ecules in both lymphoid and non-lymphoidorgans,
`
`ExpressionofB7-H1. Vhe expression of mRNAencod-
`ing B7-H1 is abundant in manytissues and organs
`2 a
`in humans*"
`and mice*!. A recent study indicates
`that the phosphatase and tensin homologue (P'TEN)-
`phosphatidylinositol-3-kinase pathway might be
`important in the post-transcriptional regulation of
`B7-H1 cell-surface expression in tumours’, B7-H1
`protein is often expressed by activatedcells including
`T cells, B cells, DCs, monocytes/macrophages*!'',
`natural killer (NK) cells, activated vascular endothe-
`lial cells”, mesenchymal stem cells” and cultured bone-
`marrow-derived mast cells". B7-H1 is also found to
`be expressed constitutively in immune-privilegedsites
`including the eyes and placenta’"’, which indicates
`that B7-H1 might inhibit self-reactive T cells or B cells
`andtherefore control inflammatory responses in these
`tissues and organs.
`Most humancancerstestedsofar express highlevels
`of B7-H1 protein™ (TABLE |). However, loworrare B7-H1
`expression is observed in most mouse and human
`tumour-cell lines". This might be owing to the lack
`of the complete cancer microenvironment incell lines
`in vitro as these tumour-cell lines can upregulate B7-H1
`protein expression in responseto cytokines", Another
`possibility, albeit less likely, is that certain molecular
`profiles have been alteredin established tumour-cell
`lines during culture. Therefore, the results obtained
`from established tumour-cell lines in vitro might
`needtobe interpreted carefully. In addition to tumour
`cells, B7-H1 protein expression has been observed
`in human tumour-associated DCs*'"’, fibroblasts"
`and T cells’.
`
`ExpressionofB7-H4, Similar to B7-H1, mRNA encoding
`B7-H4 is widely distributed in peripheral tissues’,
`However, although the expression of B7-H4cell-surface
`protein was detected in normal humanepithelial cells of
`thefemale genital tract, kidney, lung and pancreas, B7-H4
`protein was generally absent in other normal human
`
`468 | JUNE 2008 | VOLUME&
`
`This material was copied
`atthe NLM and may be
`
`www.nature.com/reviews/immunol
`
`

`

`REVIEWS
`
`Refs
`
`36,44,48
`36,44
`
`36,89
`125
`81
`36,44,86
`44
`
`126
`88
`23,36,44,87
`
`Number of B7-H1' T cells correlates with tumour size, stage and HER2! expression
`ND
`
`B7-H1 expression correlates with increased tumoursize, metastasis and poorsurvival
`B7-H1 expression by tumour cells inhibits T-cell activationin vitro
`B7-H1 expression by leukaemia cells has no effect on T-cell activationinvitro
`B7-H1' regionsof the tumour contain fewerT cells in non-smallcell lung cancer
`ND
`
`B7-H1 plasmacells inhibit T-cell activation in vitro
`B7-H1 expressionis associated with poor prognosis
`B7-H1 expression by tumourcells is associated with a decreased numberofT cells in
`the tumour and poor prognosis. B7-H1' tumour-associated dendritic cells inhibit T-cell
`function.
`
`B7-H1 expression by tumourcells is associated with a decreased numberof tumour
`T cells and poor prognosis.
`ND
`
`127
`
`36
`
`44,85,128
`36
`129,130
`
`Table 1
`
`|B7-H1 expression in human cancersandits immunological, clinical and pathological associations*
`B7-H1'* cases/
`Immunological, clinical and pathological associations
`total cases
`
`Human cancer type
`
`Breast cancer
`
`Colon cancer
`
`Gastric cancer
`
`Glioma
`
`Leukaemia
`
`Lung cancer
`Melanoma
`
`Multiple myeloma
`
`Oesophageal cancer
`Ovarian cancer
`
`Pancreatic cancer
`
`Peripheral T-cell lymphoma
`Renal-cell carcinoma
`
`Thymic neoplasm
`Urothelial cancer
`
`24/56
`16/25
`
`45/105
`10/10
`17/30
`86/87
`22/22
`
`82/82
`18/41
`82/93
`
`20/51
`
`7/11
`
`130/196
`28/34
`142/268
`
`B7-H1 expression by tumourcells is associated with poor prognosis
`ND
`B7-H1 expression by tumourcells is associated with advanced stage, recurrence and
`poor survival
`“The data for each tumour type are assembled from more than onereport. Some data have not been includedin the tableifless than 10 tumour samples were
`reported fora particular type of humancancer. ‘HERZ (also known as ERBB2 or Neu)is a tumour-assoc iatedantigenthatis expressedin about 25% of cases of breast
`cancer, Vaccines against HER2 are beingtested for cancer therapy in humans. Monoclonal antibodies specific for HER2 (such as trastuzumab(Herceptin;
`Genentech/Roche)) are approvedfor the therapy of human breast cancer. ND, not determined.
`
`somatic tissues”. Nonetheless one study did observe
`broadcell-surface expression of B7-H4 protein on mouse
`haematopoieticcells”
`. The causeofthis interspecies
`difference is unknown.
`B7-H4is commonly detectable in the human cancer
`microenvironment (TABLE 2), For example, human ovar-
`ian cancersexpress highlevels of B7-H4 protein",
`andlowlevels of soluble B7-H4 protein were foundin
`the sera frompatients with ovarian cancer’’. In addi-
`tion to tumourcells, tumour-infiltrating macrophages"
`and endothelial cells of small blood vessels” in the can-
`cer microenvironmentare also foundto constitutively
`express B7-H4.
`In summary, the current data reveal broad expression
`patterns of B7-H1 and B7-H4protein in human tumours,
`in contrasttotheirrare expressionin normaltissues. These
`dataindicate that post-transcriptional regulation could
`have acrucial role in the control of B7-H1 and B7-H4
`protein expression in normal tissues and organs, and
`that this regulatory mechanismis aberrant in tumours.
`Furtherinvestigation ofthe regulatory mechanisms and
`thesignalling pathways leading to expression of B7-H1
`and B7-H4will generate important informationfor the
`understanding of tumour immuneevasion and provide
`potential molecular targets for treating humancancers.
`
`Regulation of expression
`The tumour microenvironment contains
` a large number of
`'* Someofthese
`cytokines andinflammatory mediators
`molecules can regulate the expression of B7-H1 and B7-H4.
`
`Regulation of B7-H1 expression. B7-H1 expression can
`be induced or maintained by many cytokines**"°", of
`whichinterferon-y (IFNy) is the most potent. Established
`human tumour-cell lines rarely express B7-H1 protein
`onthe cell surface, but high levels of B7-H1 expression
`can be inducedbytreatment with IFNy in most ofthe
`cell lines tested so far". Consistent with this, IFNy can
`induce highlevels of B7-H1 expression by normalepi-
`thelial cells, vascular endothelial cells”, proximal tubular
`epithelialcells” andniyeloid DCs, It is assumedthata
`strong 1, I-cell response can induce B7-H1 expression
`by APCs andothercells through IFNy, andin turn main-
`tain the thresholdofT-cell activationtoavoidtissue and
`organ damage.In addition to IFNy, type LIFN can also
`stimulate B7-H1 expression by hepatocytes", monocytes,
`DCs"! and tumour cells (S. Wei, lL. Kryczek, L. Chen and
`W. Zou, unpublished observations). In this context,after
`virus infection, tumour-associated plasmacytoid DCs
`producelarge amounts oftypeI [PN in vitro®, which
`can in turn induce B7-H1 expression”’. Plasmacytoid
`DCspreferentially induce T,,2-cell responsesincertain
`situations’. Therefore, the expression of B7-H1 could
`potentially be stimulated in both T\,1- andT) 2-cell-
`biased conditions,although the expression andrelevance
`of B7-H1 expressionin T),1- or T,.2-cell-associateddis-
`eases remains to betested.
`In light ofits stimulatory effect on B7-H1 expres-
`sion, IFNy could thus be a ‘double-edged sword’ in
`tumour immunity. Whereas IFNy could increaseanti-
`gen processing and presentation by upregulating the
`
`Myeloid DCs
`Asubset of dendritic cells (DCs)
`that
`are lineage-negative,
`HLA DRUCD I c* (in humans)
`mononuclear cells with a
`Monocyiod appearance,
`Human myeloid DCs might be
`denved fram myeloid
`precursors (lor example,
`monocytes, macrophages ard
`CD 11e! precursors)
`
`Plasmacytoid DCs
`A subset of dendritic cells (DCs)
`thal are lineape nepalive,
`(in Humans)
`HLA-DR CD11
`mononuclear cells with a
`TICPOSCOPIC appearance
`similar to plasmablasts,
`Plasmacyloid BCs are the main
`producers of type Linterteran
`
`AMCTIIDE pie [IMMUNOLOGY
`
`This material was copied
`atthe NLM and may be
`
`VOLUME & | TUNE 2008 | 469
`
`

`

`REVIEWS
`
`Table 2|B7-H4 expression in human cancersandits immunological, clinical and pathological associations*
`B7-H4* cases/
`Immunological, clinical and pathologicalassociations
`Human cancer type
`total cases
`165/173
`240/246
`
`B7-H4 expressionis associatedwithlack of expression of progesterone receptor and HER2!
`ND
`
`Breast cancer (primary)
`Breast canc er
`(metastatic)
`
`Refs
`
`50,54
`50
`
`Lung cancer
`Ovarian cancer
`Prostate carwer
`Renal-cell carcinoma
`
`Uterine endometrioid
`adenocarcinoma
`
`35/86
`202/216
`120/823
`153/259
`90/90
`
`B7-H4 expression is more commonin patients with lymph-node metastasis
`B7-H4* tumour-associated macrophagesinhibit T-cell activation and predict poorsurvival
`B7-H4 expression by tumourcells is associatedwith disease spread, recurrence and death
`B7-H4 expression by tumourcellsis associated with poor survival
`B7-H4 expression by tumourcells is associated with weak F-cellinfiltration andhigh-risk
`tumours
`
`49,131
`31,49,51-55
`90
`56
`132
`
`than one report. Some data have not been includedin the tableif less than 10 tumour samples were
`“Thedata for each tumour type are assembled from more
`reportedfor a particular type of hurman cancer. HER? (also knownas ERBB? or Neu)is a tummour-associatedantigen that is expressed in about 25%of case sal breast
`cancer, Vaccines against HER? are being testedfor cancer therapy in humans, Monoclonal antibodies specific for HER? (such as trastuzumab(Herceptin:
`Genentech/Roche)) are approved for the therapy of humanbreast cancer. ND, not determined.
`
`expression of MHC molecules and components of the
`antigen-processing machinery",theeffects of IFNy on
`B7-H1 expression might downregulate ‘T-cell immu-
`nity. This could explain, at least partially, why IFNy
`has not beeneffective as a therapeutic agent for most
`humancancers. In addition, [FNy has been shownto
`stimulate the expressionofjndoleamine 2, 4-dioxypenase
`(IDO) and arginase®’ * on APCs. Such APCs could
`suppress anti-tumour immuneresponses. Therefore,
`it is not surprising that an increase in the numberof
`TAA-specific cytotoxic T lymphocytes (¢ “TLs) does not
`always translate into clinical regression of cancers”
`In addition, IFNy was also found to mediate CD4'
`‘T-cell loss and impair secondary anti-tumour immune
`responsesafter successful initial immunotherapyin
`tumour-bearing mouse models’*. As B7-H1 expression
`can be induced on APCs and multiple humanepithe-
`lial tumours, stimulation of B7-HI expression could be
`a strategy used by the tumourto evade T-cell-mediated
`tumour immunity.
`
`Regulation of B7-H4 expression. The regulation of
`B7-H4expression has only been studied in the human
`system. Interleukin-6 (IL-6) andIL-10 stimulate B7-H4
`expression by monocytes, macrophages and myeloid
`DCs. The DC-differentiation cytokines, GM-CSF
`(granulocyte/macrophage colony-stimulating factor)
`andIL-4, decrease B7-H4 expression bythesecells
`induced by IL-6 and IL-10 (REFS 41.55,
`/4) (FIG. 2). TFNs
`seemto have a minimal effect on the induction of B7-H4
`expression, in contrast to the induction of B7-H1 expres-
`sion". In humanovariancancer, tumour-associated T)
`cells trigger macrophages to produce IL-6 andIL-10, and
`these cytokines in turn stimulate B7-H4 expression by
`APCsin anautocrine and/or paracrine manner”. High
`levels of IL-6 and IL-10, but not GM-CSF andIL-4, are
`detected in the ovarian tumour microenvironment,
`Therefore, this dysfunctional cytokine network in the
`tumour microenvironment enables APCs to express
`B7-H4. Interestingly, IL-4, IL-6, IL-10 and GM-CSF
`have no regulatory effects on B7-H4 expression on
`tumourcells, which indicates that B7-H4 on tumour
`
`cells and B7-H4 on APCs might befunctionallydistinct
`andbedifferentially regulated’!”. Collectively, B7-H |
`and B7-H4 are regulated by distinct mechanisms.
`Thesedifferential regulatory patterns have important
`implications in the generation and amplification of
`tumour-specific immunity.
`
`Evasion of tumour immunity
`The physiological functions of inhibitory B7-family
`members areto limit, terminate and attenuate‘l-cell
`responses, by which theyprevent T-cell hyperactivation
`andavoid tissue and organ damage during immune
`responses!”". B7-H1-deticient ’" and B7-H4-deficient
`mice have been generated and reported in the pub
`lishedliterature. The inhibitory B7 molecules can be
`induced in responseto inflammation and potentially
`to broader