Immunology,
`Infection, and
`Immunity
`
`
`EDITEDBY
`
`Gerald B. Pier
`ChanningLaboratory, Brigham and Women’s Hospital
`and
`Harvard Medical School, Boston, Massachusetts
`
`Harvard Medical School, Boston, Massachusetts
`
`Jeffrey B. Lyczak
`Channing Laboratory, Brigham and Women’s Hospital
`and
`
`Lee M. Wetzler
`Evans Biomedical Research Center
`and
`Division ofInfectious Diseases, Department of Medicine,
`Boston University School of Medicine
`and
`Boston Medical Center, Boston, Massachusetts
`
`fa
`
`ASM
`PRESS
`
`WASHINGTON,D.C.
`
`
`
`
`PGR2019-00002
`UNIV. CHICAGO EX. 2024
`
`
`Genome& Co. v. Univ. of Chicago
`
`
`
`

`

`Address editorial correspondenceto ASMPress, 1752 N St. NW,Washington, DC
`20036-2904, USA
`
`Send orders to ASM Press, P.O. Box 605, Herndon, VA 20172, USA
`Phone: (800) 546-2416 or (703) 661-1593
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`
`Copyright © 2004 ASM Press
`American Society for Microbiology
`1752 N St. NW
`Washington, DC 20036-2904
`
`Library of Congress Cataloging-in-Publication Data
`
`Immunology,infection, and immunity / edited by Gerald B.Pier,Jeffrey
`B. Lyczak, Lee M. Wetzler.
`p-;.cm.
`Includes bibliographical references and index.
`ISBN 1-55581-246-5 (hardcover)
`1. Immunology. 2. Infection.
`[DNLM:1. ImmuneSystem. 2. Immunity, Cellular. 3. Immunologic
`Diseases. 4. Infection. QW 504 1333 2004]
`I. Pier, Gerald Bryan.II.
`Lyczak,Jeffrey B. III. Wetzler, Lee M.IV.Title.
`QR181.1443 2004
`616.07°9—dc21
`
`2003002554
`
`10987654321
`
`All Rights Reserved
`Printed in the United States ofAmerica
`
`

`

`
`
`Cancer and the
`ImmuneSystem
`Lisa H. Butterfield, Stephen P. Schoenberger,
`and Jeffrey B. Lyczak
`
`A Genetic and physiological aspects of tumorigenesis
`A Immunerecognition of tumors: tumor antigens
`A Immunecell types that respondto tumors
`A Cancer immunotherapies
`
`
` topics covered
`
`
`/ ancer can be consideredas a disease resulting from the progressive cel-
`lular expansionofa single cell whose progeny have escaped from nor-
`
`mal regulatory mechanisms controlling cell division and homeostasis.
`> Atfirst glance, cancer appearsto bea vast and bewilderingarray ofdis-
`eases, with as manydifferenttypes ofcanceras there are types ofcells in the body
`(Table 24.1). There are, in fact, over 100 different types of cancer known, and
`subtypesofthese disease states can be found within specific organs. As methods
`for the treatmentandprevention ofinfectious and cardiovascular diseases im-
`prove, canceris emergingas the leading causeofdeathin industrialized countries
`(Fig. 24.1). Although conventional cancer
`treatments such as surgery,
`chemotherapy, andradiation have greatly enhanced patient survival, manipula-
`tion ofthe immuneresponseto cancercells to promotetheir destruction remains
`an important and increasingly realistic goal for physicians. Immunological con-
`trol ofcancers could conceivably playarolein the eradication ofprimary tumors
`and disseminated metastases as well as the residual cancercells that remain after
`conventional treatment regimens. Theidealresult of immunotherapy would be
`thespecific eradication ofcancercells with minimal damageto normal hostcells.
`However, almost by definition a tumorcell has escaped immunologic recogni-
`tion andprogressed to cancer becausethe affected patient’s immunesystem did
`not control tumor growth. Attainmentofthe goal of effective immunotherapy
`for tumorsrequires an understanding ofhow the immune system bothfails to re-
`spondto cancercells and has the potential to respond andthe ways in which this
`responsecanbestrategically manipulated.
`
`573
`
`

`

`Table 24.1 Nomenclature ofseveral types of cancer
`
`Normal tissue WEAReiim atte)aSTiCeTeal
`
`Bloodvessels
`Angioma
`Angiosarcoma
`Bone
`Osteoma
`Osteosarcoma
`Cartilage
`Chondroma
`Chondrosarcoma
`Epithelium
`Papilloma
`Carcinoma
`Glandularepithelium
`Adenoma
`Adenocarcinoma
`Liver hepatocytes
`Hepatoma
`Hepatocarcinoma
`Skeletal muscle
`Rhabdomyoma
`Rhabdomyosarcoma
`
`Smooth muscle Leiomyosarcoma Leiomyoma
`
`“Benign tumorsare anatomicallyrestricted to their originaltissuesite.
`Malignant tumors are capableofspreading (metastasis) to distantsites.
`
`Figure 24.1 Cancer deaths in the United States, comparingthe period from 1950 to 1969 with the period
`from 1970 to 1994, Data are for white malesofall ages, are grouped according to county, and are expressed as
`the numberofcancer-related deaths per 100,000 person-years. Thevertical black bar in the center of each
`graph showsthe nationwide average of cancer-related deaths. Data are from the National CancerInstitute’s
`
`1970-1994
`
`Abbeville, SC
`Acadia, LA
`Accomack, VA
`Ada, ID
`Adair, IA
`Adair, KY
`Adair, MO
`Adair, OK
`Adams, CO
`Adams, ID
`Adams, IL
`Adams, IN
`Adams, IA
`Adams, MS
`Adams, NE
`Adams, ND
`Adams, OH
`Adams, PA
`Adams, WA
`Adams, WI
`Addison, VT
`Aiken, SC
`Aitkin, MN
`Alachua, FL
`Alamance, NC
`Alameda, CA
`Alamosa, CO
`Alaska
`Albany, NY
`Albany, WY
`Albemarle, VA
`Alcona, MI
`Alcorn, MS
`Alexander, IL
`Alexander, NC
`Alfalfa, OK
`Alger, MI
`Allamakee, LA
`Allegan, MI
`Allegany, MD
`Allegany, NY
`Alleghany, NC
`Alleghany, VA
`Allegheny, PA
`Allen, IN
`Allen, KS
`Allen, KY |
`Allen, LA
`Allen, OH
`Allendale, SC
`143.71
`
`160.01
`
`176.31 - 192.6
`National average = 184.46
`
`208.9
`
`225.2
`
`183.42
`
`Atlas of Cancer Mortality, which can be viewed at http://www3.cancer.gov/atlasplus/. 1950-1969
`
`Abbeville, SC
`Acadia, LA
`Accomack, VA
`Ada, ID
`Adair, [A
`Adair, KY
`Adair, MO
`Adair, OK
`Adams, CO
`Adams, ID
`Adams, IL
`Adams, IN
`Adams, IA
`Adams, MS
`Adams, NE
`Adams, ND
`Adams, OH
`Adams, PA
`Adams, WA
`Adams, WI
`Addison, VT
`Aiken, $C
`Aitkin, MN
`Alachua, FL
`Alamance, NC
`Alameda, CA
`Alamosa, CO [
`Alaska
`Albany, NY
`Albany, WY
`Albemarle, VA
`Alcona, MI
`Alcorn, MS
`Alexander, IL
`Alexander, NC
`Alfalfa, OK
`Alger, MI
`Allamakee, LA
`Allegan, MI
`Allegany, MD
`Allegany, NY
`Alleghany, NC
`Alleghany, VA
`Allegheny, PA
`Allen, IN
`Allen, KS
`Allen, KY
`Allen, LA
`Allen, OH
`Allendale, SC
`166.05
`
`574
`
`200.79 4 218.15
`National average = 209.47
`
`235.52
`
`252.89
`
`

`

`
`
`CancerIs a Disease of Genes
`
`Through intensive research efforts over the past 25 years,
`cancer is now understood asa series of defects in the
`molecular machinery that governs proliferation and
`homeostasis in nearly all cell types. Normal cellular
`growth within an organism is kept in balance by various
`regulatory circuits that govern the rate at whichcells di-
`vide, differentiate, and die. Some of these regulatory cir-
`cuits are intrinsic to the cell whereas others are coupled to
`the signals that cells receive from their surrounding mi-
`croenvironment(Fig. 24.2). Cancerarises through a pro-
`cess termed neoplastic transformation that occurs when a
`
`Figure 24.2 Schematic diagram of a typical eukaryotic cell showing
`the factors or conditions that regulate its growth. Exogenousfactors,
`stimuli, or cues are shownin black type. Growth inhibitory factors
`andevents are shownwith red arrows. Growth stimulatory factors and
`events are shown with green arrows. TNF-R, tumornecrosis factor re-
`ceptor; CAM,cell adhesion molecule; FAK, focal adhesion kinase; RB,
`retinoblastoma tumorsuppressor protein; TF, transcription factor.
`
`Cancer and the Immune System
`
`575
`
`Mutationsin
`+ Growthfactor
`receptor
`* Protein kinase
`
`Mutationsin
`* Cell cycle regulators
`+ Additional mutations
`
`+ Loss of CAMs
`* Overproduction
`of matrix proteases
`
`Ya%ohs
`
`Benign tumor
`(genetically
`unstable)
`
`Malignant
`tumor
`(metastatic)
`
`Normal
`cell
`
`Mutant,
`neoplastic cell
`(growth
`dysregulated,
`hyperproliferative)
`
`Figure 24.3 The multistep process of tumorigenesis. The cell, which
`is originally normal (at the left), undergoes several genetic changesin
`a stepwise fashion. Each genetic changeresults in a phenotypic alter-
`ation that favors unregulated growth, exemption from apoptotic sig-
`nals, genetic instability, and metastasis (ability to spread from its origi-
`naltissue site to other remotetissues ofthe host).
`
`
`
`Integrins,
`cadherins
`
`Growtharrest,
`
`
`
`
`
`
`migration arrest poptosis Growth factor
`
`cell undergoesa series of genetic alterations and acquires
`the capability to escape these regulatory mechanisms.
`
`This processis thoughtto occurinadiscrete stepwise pro-
`Neighboring
`cell
`cess involving the age-related incidence of four to seven
`stochastic events that drive the transformation of a nor-
`mal cell into highly malignantclonal derivatives (Fig.
`24.3). This processis similar to a Darwinian modelof evo-
`lution, in that each genetic change confers a growth ad-
`vantagethat leads to overrepresentationofthealteredcell.
`The successive and heritable nature of cellular transfor-
`mationevents is supportedby histological analysesof pre-
`cancerouslesions revealing cells that appear to represent
`intermediate steps in the pathway between normal and
`transformed cells.
`Another knownsituation that establishes a genetic ba-
`sis for cancer comes from studies thathave identified cer-
`tain mutant forms of normal genes that predispose indi-
`viduals to be at a greaterrisk for a given type of cancer. For
`example, womenhave a 10% lifetimerisk for developing
`breast cancer, but amongthese patients are a small per-
`centage with mutations in one of two genes, BRCA1 and
`BRCA2,thatgreatly increase therisk of developing breast
`cancer. However, even carrying a high-risk mutation in
`the BRCA genes doesnotinevitably lead to breast cancer
`as 20 to 30% of women with mutant genes never develop
`this disease. Thusthere are clearly modifier genes that can
`counteractthe negative effects of the mutant genes, Other
`genetic predispositions to cancer include colon cancer as-
`sociated with the adenomatous polyposis coli gene on
`chromosome5; hereditary nonpolyposis colon canceras-
`sociated with DNA mismatch repair genes on chromo-
`somes 2, 3, and 7; melanoma associated with the
`
`
`
`receptor
`
`
`
`oY Growth factor
`
`
`
`

`

`
`
`576
`
`~=Chapter 24
`
`CDNK2Agene on chromosome9; testicular cancer asso-
`ciated with the TCGI gene on the X chromosome;and the
`Li-Fraumeni multiple cancer syndromearising from mu-
`tations in the T7P53 gene on chromosome17.
`
`Genetic Changesin TransformedCells
`Modern molecular biology hasallowed thevastcatalog of
`different cancers described over the past century to be
`represented by an equally broad spectrum ofcancer geno-
`types. Although the genetic defects permitting such au-
`tonomous growth are numerous, certain molecular
`themes have becomeapparent, allowing these defects to
`be organized into classes, according to what growth-
`regulatory mechanismis affected (Table 24.2). Any defec-
`tive gene whosealtered function promotes the conversion
`of anormalcell to a tumorcell is termed an oncogene. The
`normal version of the same gene is termed a proto-
`oncogene to denote that the geneis capable (through mu-
`tation) of givingrise to a cancer-causing oncogene.Figure
`24.4 depicts several ways that a proto-oncogene can be
`converted to an oncogene. Conversion can occur by either
`point mutation, frameshift mutation, or chromosomal
`translocation. The consequences of these genetic events
`can either beloss of the gene’s original function, enhance-
`mentofits original function,or a changein the gene’s rate
`of transcription. In somecases, the proto-oncogeneis a
`growth-promoting gene, and through either increased
`transcription or increased activity of its protein product,
`the oncogene causes unregulated cell division. An exam-
`ple of this is the Src protein tyrosine kinase shown in Fig.
`24.4A. In other cases, the proto-oncogene normally serves
`a role in preventingor delayingcell division, anda loss-of-
`function mutation in the oncogene removesthis regula-
`tory mechanism,resulting in inappropriatecell division.
`Proto-oncogenesthatfall into this category are sometimes
`referred to as turmor-suppressorgenes or anti-oncogenes. An
`example of a tumor suppressor gene is the p53 protein,
`which normally functionsto arrest the cell division cycle
`while DNArepair is proceeding, ensuring that existing
`
`mutationswill be corrected and chromosomal integrity
`restored before DNAsynthesis proceeds.
`Another way that tumorcells attain the ability to pro-
`liferate in an uncontrolled fashion is by becoming inde-
`pendentof the growth signals on which normalcells are
`dependent. Manyofthe oncogenesassociated with cancer
`act by mimicking normal growthsignals in various ways
`(Table 24.3). This can occur by increased expression of
`soluble growth factors or growth factor receptors that can
`lead to autocrinestimulationofcell division. Cancercells
`often have alterations in the downstream cytoplasmicsig-
`naling components of growth factor receptors, leading to
`the constitutive transmission of growth signals, even in
`the absenceof the actual growth factor. Examplesofthis
`type of change are the numerous point mutations found
`in ras oncogenesthatlead to their constitutive activation
`and the genetic translocationsthat lead to chronic myel-
`ogenous leukemia (CML). CMLis due to a chromosome
`translocation knownast(9;22), which results from move-
`ment of the breakpoint cluster region (ber) on chromo-
`some22 to the c-abl gene on chromosome9.This translo-
`cation gives rise to what is knownas the Philadelphia
`chromosome. Theprotein productofthis fusion, the Abl
`tyrosine kinase, appears to be necessary for oncogenic
`transformation of CMLcells. The wild-type c-Abl tyro-
`sine kinase does not transform cells. A major advance in
`cancer chemotherapy has recently occurred with theli-
`censingof Gleevec (also referred to as STI571 or imatinib
`mesylate), which is a small molecule that specifically in-
`hibits the tyrosine kinase activity of the Bcr-Abl fusion
`protein.
`The ability ofa cancercell’s growth program to be freed
`from its dependence on environmental signals does not in
`itself guarantee expansive growth. Work by Leonard
`Hayflick and colleaguesin the 1960s revealed thatcells in
`culture havea finite replicative potential and enter a non-
`proliferative “senescent”state after having achieveda cer-
`tain numberof doublings(referred to in some olderliter-
`ature as the “Hayflick number”). Cellular senescence can
`
`Table 24.2 Biochemical basis for stimulation ofcell growth by oncogenes
`ioecomce telecrits
`product
`c-Src"
`EGF-R
`
`Normal function of proto-oncogene
`Protein tyrosine kinase
`Growthfactor receptorwith intrinsic kinase activity
`
`Oncogene
`v-srce®
`v-erbB
`
`Growth factor
`PDGF
`v-sis
`Signaling molecule
`Ras
`Ha-ras
`DNA-binding kinase; inhibitor oftranscription
`Abl
`y-abl
`Transcription factor
`Myce
`mye
`““v-” indicates a viral analog of the gene; “c-” indicates a normal cellular version of the gene.
`
`Alteration in oncogene
`Constitutively active
`Does not contain growth factor binding domain;
`kinase domain is constitutively active
`Overexpression
`Constitutively active
`Loss of inhibitory activity
`Overexpression
`
`EE
`
`

`

`
`Cancer and the Immune System
`577
`
`A
`
`sre gene
`
`Tyr 2?
`
`Substitution of
`portion ofsre
`with viral
`genome
`
`
`
`
`
`src gene
`
`Gln Tyr Gln
`CAG TAC CAG
`
`Gln Ser Gln
`CAG TCC CAG
`
`Point
`mutation
`
`sre gene
`
`Provirus
`
`B
`
`Translocation.
`
`Figure 24.4 Conversion of a normal
`proto-oncogene to a cancer-promot-
`ing oncogene can result from changes
`in expression ofthe proto-oncogene
`or from alterations in the activity of
`the protein encoded bythe proto-
`oncogene. (A) The sre proto-onco-
`gene encodesaprotein tyrosine ki-
`nase. Point mutation at the 3' end of
`the generesultsin loss ofthe tyrosine
`at position 527 (Tyr**”) thatis crucial
`for negative regulation of the kinase’s
`enzymaticactivity. The regulatory ty-
`rosinealso can belost by insertion of
`viral DNAthat interrupts the src gene
`coding sequenceprior to Tyr”. In
`either case, the mutant form ofthe
`kinase is constitutively active. (B) The
`myc proto-oncogene encodes a tran-
`scription factorthat helps regulate
`cell division andcell death. Chromo-
`somaltranslocation betweenthe q
`arm of chromosome 8 and the q arm
`of chromosome14places the myc
`gene in the middle ofthe Ig heavy
`chain locus, enhancing transcription
`of the myc gene in B cells. This results
`in dysregulated cell division and the
`formation of B lymphomas.(C) In-
`sertion of the human T-lymphotropic
`virus type | (HTLV-1) provirus near
`the myc proto-oncogene causes over-
`expression of myc, driven by strong
`enhancerelementsin theviral long
`terminal repeats (LTRs). The virus
`encodes a protein called Tax (1) that
`activates (2) several host cell tran-
`scription factors (TF). The activated
`TFs then enhancetranscription (3)
`from the nearby myc promoter (Pynye
`[yellow oval]) by bindingto the
`proviral LTR.
`
`Chromosome date
`
`ad
`
`8
`
`14
`
`sekae
`
`myc-Ig
`Chromosome
`14q*
`
`
`
`HTLV-1 provirus
`
`be overcomebydisabling anti-oncogenes such as p53 and
`pRB,thusallowing the cells to proceed through additional
`roundsofdivision. Because this dysregulation uncouples
`cell division from the normal mechanisms of DNArepair,
`
`the progeny of these cells accumulate chromosomalab-
`normalities. These cells can reach a state called “crisis,”
`which is characterized bythe large-scale cell death and the
`rare emergence of an immortalized variant that acquires
`
`Release from antiproliferative signals
`Acquire blood supply
`
`Loss of function of regulatory proteins
`Activate local angiogenesis
`
`Table 24.3 Characteristics acquired during emergence of a tumorcell
`
`Genetic example(s) of mutations and
`
`Characteristics CittaeMm ead)Witt4TTR
`
`
`Growth signal independence
`Mimic normalsignals via altered
`Src, Ras: constitutive signaling; Her-2/Neu:
`signaling components
`initiates signal withoutligand p53; RB:cell cycle
`proceeds despite DNA damage
`Fas:cell does not respondto pro-apoptotic signals
`Vascular endothelial growth factor
`Angiomodulin
`Plasminogen activator, matrix metalloproteinase
`Integrins
`CD44,focal adhesion kinase
`
`Spread to other anatomic sites (metastasis)
`
`Degrade extracellular matrix
`Downregulate cell adhesion molecules
`Modification ofcell adhesion apparatus
`
`
`
`

`

`578=Chapter 24
`
`
`
`the capacity for limitless replicative potential. The molec-
`ular basis for cellular immortalization in cancer cells is
`thought to betheir ability to maintain the length of the
`structures called telomeres that are found at the ends of
`chromosomes. Telomeres consist of several thousandre-
`peats of a short 6-base-pair (bp) sequence that are pro-
`gressively shortened by 50 to 100 bp with each successive
`cell division. Once telomeres are reducedin length to be-
`low a crucial threshold length, they can no longerprotect
`the chromosomes from end-to-end fusions with other
`chromosomes, and this may underlie the many karyotypic
`aberrationsassociated with crisis. Telomeres are normally
`maintained by an enzymecalled telomerase, which cat-
`alyzes the addition ofhexanucleotide repeats to the ends of
`telomeric DNA. Telomeraseis not expressed in senescent
`normalcells, but numerous tumor samples have been
`foundto expressthis enzymeathighlevels, suggesting that
`cancercells exploit this enzymefor their ownbenefit.
`Liberated from cellular senescence and capable of au-
`tonomousproliferation, the growing tumor mass requires
`a supply of oxygen and nutrients to sustain its growth, a
`need which becomesprogressively more urgentas the mass
`of the tumorincreases. The processofangiogenesis leads to
`the formation of blood vessels and capillaries within a tis-
`sue andis carefully regulated by counterbalancing negative
`andpositive signals. Someofthesesignals are mediated by
`soluble factors interacting with their receptors thatare able
`to either promoteor inhibit blood vessel growth. Others in-
`volve the interaction of cellular proteases with integrin
`
`moleculesas well as elementsofthe extracellular matrix and
`can mediate the mobility ofvascular endothelial cells. The
`ability ofsolid tumors to induce angiogenesis seemsto stem
`from several factors (Fig. 24.5). First, the physical expan-
`sion of the tumorperse can activate the thrombin cascade
`by causing local tissue injury. This enzymatic cascade in-
`creases vascular permeability, activates matrix metallopro-
`teases, and triggers production of vascular endothelial
`growth factor (VEGF). Second, some tumors can them-
`selves produce VEGF, enhancing the angiogenic process.
`The ability ofan incipient cancerto activate the “angiogenic
`switch”from vascular quiescenceto sustained angiogenesis
`appearsto represent an importantstep in the tumorigenic
`process. The work of Judah Folkman and colleagues has
`demonstrated that a tumor’s dependence on angiogenesis
`can be exploited for therapeutic purposes,a finding that has
`led to the development of novel drugs that contro] the
`bioavailability of pro- and antiangiogenic factors and
`thereby inhibit tumor growth.
`For cancer cells to thrive and expand, the increased
`growth rate must be matched by a decrease in therate at
`which they die. The removalofcells in vivo normally oc-
`curs through programmedcell death or apoptosis, which
`acts the same in nonhematopoietic cells as it does in
`hematopoietic cells such as lymphocytes. Apoptotic cells
`and their remains are ultimately engulfed by phagocytes.
`Escape from apoptosis is emergingas a key feature of can-
`cer, with mounting evidence coming from both animal
`
`Figure 24.5 Solid tumors induce angiogenesis
`and direct new bloodvessels to grow into the
`tumor, providing the tumorwith nutrients and
`waste removal. Growing tumor masses stimu-
`late angiogenesis by causing local tissue injury
`(1), thusactivating the thrombin cascade (2).
`Thrombin activates endothelial cells and
`platelets (3) to produce matrix metallopro-
`teases (MMPs), VEGF,andtissue factor (TF).
`VEGFdirects growth andelongation of vascu-
`lar endothelium (4). MMPsdissolve extracellu-
`lar matrix (ECM) componentsto allow growth
`of new vascular endothelium (5). TF stimulates
`further production of thrombin,setting up a
`positive feedback loop (6), Some tumorsse-
`crete VEGFto enhancethis process (7).
`Reprinted from D. E, Richard et al., Oncogene
`20:1556-1562, 2001, with permission.
`
`studies and clinical human tumorbiopsies. Studies with Vascular endothelium
`
`VEGF
`
`ny
`
`
`@ Compression and
`injury to localtissue
`
`

`

`
`Cancer and the Immune System
`579
`
`mice have revealed that apoptosis pathwayscan beinter-
`rupted in tumorcells at several levels. In somecases, the
`tumorcells lose expression of a surface receptor protein
`that normally receivessignals initiating apoptosis. Tumor
`cells that have lost expression of the CD95 (Fas) are not
`capable of responding to the protein CD95L (Fas ligand
`[FasL]), which cytotoxic T lymphocytes (CTLs) useto in-
`duce apoptosis oftheir targets. In other cases, the bio-
`chemicalsignaling pathway that mediates apoptosis is ei-
`ther disabled or dysregulated to favor survival of the
`tumorcell. In Burkitt’s lymphoma, a tumor derived from
`lymphocytes, the transformed cells overexpress the anti-
`apoptotic protein Bcl-2. Thesecells are highly resistant to
`several cytotoxic mechanisms.
`Most tumorsarise by the neoplastic transformation of
`a cell in a solid tissue andare thereforeinitially confined
`to a discrete anatomical location. In manycases, however,
`cells from the tumoracquire the ability to detach from the
`tumor mass and invade adjacenttissues anddistantsites
`in a process called metastasis. These distant colonies are
`called metastases or secondary tumors and accountfor over
`90% of human cancer deaths. Metastasis allows tumor
`cells to expandto new areas wherenutrients and space are
`notlimiting and frequentlyresults in the growth oftumor
`masses in other tissues or organs whose normal function
`is disrupted as a result of tumor growth. The metastatic
`spread of cancer is a complex, incompletely understood
`process involving changes in the expression of genesthat
`tether a cell to its surroundings, such asintegrins, tissue
`homing molecules, and extracellular proteases. Some-
`times the newly formed metastases can conscript normal
`hosttissue into the metastatic process byutilizing factors
`they produce such as matrix-degrading proteases or
`growth factors to promote tumorgrowth.
`
`The ImmuneResponse to Cancer
`Tt has been more than 100 years since Paul Ehrlichfirst
`suggested that tumors could be destroyed by immune
`mechanisms. On thebasis of this proposition, scientists
`began studyingthe interaction between immunecells and
`tumorsin hopes of amplifying antitumor immunity as a
`meansoftreating cancer. Early experimental studies of
`the immuneresponse to tumors focused on the out-
`growth versusrejection of tumorfragments transplanted
`between outbred mice. Tumorrejectionin these cases was
`thoughtto reveal the existence of tumor-specific antigens
`and suggested that the immunesystem could beused to
`control cancer. However,in the 1930s Peter Gorer showed
`that the rejection observed in these experiments was actu-
`ally directed againstthe dissimilar major histocompatibil-
`
`
`
`ity complex (MHC) antigenson thegraft and could not be
`distinguished from tissue rejection in general. It was only
`wheninbredstrains of mice becameavailable thatcritical
`investigation into the immunogenicity oftumors could be
`undertaken. Tumors from one mouse would usually grow
`in a second mouseif the two mice wereof the samestrain
`and hence shared MHCantigens, since the tumor would
`be seenas “self tissue” by the genetically identical recipi-
`ent mouse (Fig. 24.6A). However,if the recipient mouse
`was ofa different strain and MHCtype than the donor
`mouse, the tumor would berejected by the recipient
`mouse. In the 1940s and 1950s, chemical carcinogens
`were used to induce tumors that could be excised (i.e.
`surgically removed), inactivated for growth, and then
`used as vaccines to immunize other mice of the same
`strain type. These studies demonstrated that sometimes
`such tumors expressed antigens (called tumor-specific
`antigens [TSAs]) that could invoke protective immunity
`and prevent vaccinated mice from acquiring the same
`type of tumorat a later time (Fig. 24.6B). It was later
`shownthat this protective immunity could be induced
`within an individual animal and, importantly, could be
`transferred from a vaccinated mouseto a naive (unvacci-
`nated) mouse by lymphocytes obtained from the immu-
`nized donor. The TSAs expressed by mutagen-induced
`cancers appeared to be unique to each tumorin that im-
`munization with a given tumorable to conferprotection
`from challenge with the identical tumorcould not protect
`animals from challenge with morphologically similar tu-
`mors derived from a separate site even when the second
`tumor was induced by the same chemical agent. Subse-
`quent studies in the 1960s showed that somevirally in-
`duced tumors express TSAsthatare identical to those ex-
`pressed by other tumorsinduced by the samevirus but are
`distinct from the TSAs expressed by tumors induced by
`other viruses. We now knowthatsuch virus-specific TSAs
`are actually products of the viral genomethat are ex-
`pressedin every cell infected by a given virus. Target anti-
`gens have been identified at the molecularlevelfor a vari-
`ety of tumors. Theexistence of tumor-specific antigens
`and their immunogenicity are key factors determining the
`usefulness of immunotherapy against any given tumor.
`
`Mechanismsof Antitumor Immunity
`Classes of Tumor Antigens
`The molecular identification of tumor antigens has pro-
`vided importantinsights into the immuneresponseto can-
`cer and remainsa key factor in the developmentofantitu-
`mor immunotherapies. Antigens that are unique to a
`tumor representa moleculartarget that the immune system
`
`

`

`580=Chapter 24
`
`
`
`Tumor excised
`
`|®
`
`Strain A
`mouse with
`tumor
`
`Strain A a,
`
`recipient
`
`Ry
`
`Strain B
`
`=) recipient
`
`Tumordevelops
`
`No tumordevelops
`
`Strain A mouse |
`with chemically
`
`Strain A mouse 2
`with chemically
`
`|
`|TumorYexcised
`
`used as vaccine
`
`Strain A
`
`A
`
`wo
`
`antigen-specific immuneprotection against transplanted
`tumors. (A) A tumor transplanted from one mouseto an-
`
`Figure24.6 Useofinbredmousestrainstodemonstrate
`otherwillusuallygrowin the recipientmouseifthedonor
`
`No tumordevelops
`
`Tumor develops
`
`can use to recognize andspecifically destroy a tumor. These
`antigensareclassified accordingto their pattern of expres-
`sion on tumorcells and on normal, nontransformedcells.
`
`TSAs
`TSAsare the ideal antigenic targets for an immune-based
`cancer therapy. An immuneresponse against suchan anti-
`gen holds the promiseof attacking the tumor while spar-
`ing normal,healthy cells. TSAs are formed anytimea pro-
`tein produced bythe tumorcells is qualitatively altered so
`that the protein has a sequence uniqueto the tumor. One
`example of this would be a tumorcell protein produced
`from a gene harboring one or morepoint mutations. An-
`other example wouldbeviral proteinsin a virally induced
`tumor.Since cancer is characterized by genomicinstabil-
`ity, it is not unlikely that a tumorcell will eventually begin
`to producea gene productthatis unlike any expressed by
`
`normalhostcells. From the standpoint of antitumor im-
`munotherapy, TSAsare attractive becauseoftheir unique-
`ness. Even othercells that bear mutations in the samepro-
`tein as the tumorare extremely unlikely to bear the exact
`same mutations. This benefit, however, is also a liability.
`Since TSAsare uniqueto each newly arising tumor,it can-
`not be assumedthat any one tumorexpresses a therapeu-
`tically useful TSA,and so the presence ofTSAs mustbe de-
`termined ona case-by-case basis.
`An interesting type of TSA expressed by T-cell and B-
`cell cancers is represented by the idiotype antigenic deter-
`minants on the T-cell receptor or the membrane im-
`munoglobulin expressed by the tumorcells. Leukemias
`and lymphomasare typical manifestations of lymphoid
`cell cancers. It has been possible to remove the tumorcells
`and makeanti-idiotypic antibodies and CTLsagainst tu-
`mor-specific idiotopes and use these to treat the cancer.
`
`
`
`induced tumor Y
`|
`induced tumor X
`TumorXexcised |
`A portion oftumor X
`.'.
`t iskilledbyirradiation
`| Killed tumorXcells
`ree
`
`Vaccinated Sane
`challenged with live
`
`“vaccinated mouse
`challenged with live
`
`|
`|
`aS
`
`and recipient miceare of the same strain, since the tumor
`will appearasself tissue to the immunesystem ofthe re-
`cipient. However,the transplanted tumor will always be
`rejected by the immunesystem of the recipient mouseif
`the donor andrecipientare ofdifferent strains. (B) Chem-
`ically induced tumors sometimes express antigens that are
`the result of mutagenesis and are unique to each tumor
`cells from tumor Y
`(TSAs). Killing tumor X from mouse|allowsit to be used
`cells from tumor X
`as a vaccine. If tumor X expresses a TSA, then a mouse
`vaccinated against tumor X will subsequently be protected
`against challenge with live cells from tumorX. This pro-
`tection is antigen specific, since the vaccinated mouseis
`not protected from challenge with live cells from tumor Y.
`
`

`

`
`
`
`
`Cancer andthe Immune System
`
`581
`
`However,as there are no other knowncell types that pro-
`duce anytype of surface epitope analogousto idiotopes,it
`is likely that targeting of these types of TSAswill be lim-
`ited to lymphoid cancers.
`
`TAAs
`In many cases, a tumorwill possess no unique antigens
`that the host’s lymphocytes can recognizeor will possess
`such antigens but fail to express them at a high enough
`level for antigen-specific recognition to occur. In such
`cases, tumors maybe recognized by the immunesystem on
`the basis of quantitative changes in their protein expres-
`sion profiles. These antigens are not tumorspecific butare
`termed tumor-associated antigens (TAAs) (Table 24.4).
`Oncofetal antigens are one prime example of a TAA. These
`antigens are encoded by genes expressed during embryo-
`genesis and fetal development but are transcriptionally
`silent in the adult, These genes encode proteinsthatlikely
`play a role in the rapid growth of embryoniccells and have
`been reactivated to perform the same function in the
`rapidly growing tumor. The most prominentgroupof on-
`cofetal antigens are knownasthe cancer-testis antigens be-
`cause in addition to being expressed by cancercells, they
`are also expressedin thetestis in normal males. Examples
`include the MAGEsuperfamily (made up of family mem-
`bers designated MAGE-A, MAGE-B, MAGE-C, MAGE-D,
`and necdin) whose members werefirst described in
`melanomabutlater shown to be expressed by numerous
`cancers, including lung, head and neck, and bladder tu-
`mors. There are over 50 cancer-testis antigens known,with
`the T-cell epitopes for manyof them identified.
`Anotherclass of TAAsaretissue-specific differentiation
`antigens, proteins that are normally expressedin thecells
`from which the cancerarises and that continue to be ex-
`pressed following neoplastic transformation. Thus these
`antigens identify the tissue of origin of the tumor. The
`best-characterized examples of these are represented by
`the melanomadifferentiation antigens gp100, Melan-
`A/MART-1, and tyrosinase. These genes encodeproteins
`that function within the melanin biosynthetic pathway of
`skin cells and are also expressed by many pigmented
`
`Table 24,4 Comparison of TSAs and TAAs
`arTTY
`TSAs
`
`Expressed bynormal
`cells
`
`No
`
`ag.)
`
`Yes
`
`Nonself or