`
`EDFTE[)BY
`
`Gerald B. Pier
`
`Charming Laboratory, Brigham and Women’s Hospital
`and
`
`Harvard Medical School, Boston, Massachusetts
`
`Jeffrey B. Lyczak
`Charming Laboratory, Brigham and Women’s Hospital
`and
`
`Harvard Medical School, Boston, Massachusetts
`
`
`
`Lee M. Wetzler
`Evans Biomedical Research Center
`and
`
`Division of Infectious Diseases, Department of Medicine,
`Boston University School of Medicine
`and
`
`Boston Medical Center, Boston, Massachusetts
`
`(A
`
`ASM
`PRESS
`
`WASHINGTON, DC.
`
`
`
`
`UNIV. CHICAGO EX. 2024
`
`
`PGR2019-00002
`
`Genome & Co. v. Univ. of Chicago
`
`
`
`

`

`Address editorial correspondence to ASM Press, 1752 N St. NW, Washington, DC
`20036-2904, USA
`
`Send orders to ASM Press, PO. 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 I edited by Gerald B. Pier, Ieffrey
`B. Lyczak, Lee M. Wetzler.
`p. ; cm.
`Includes bibliographical references and index.
`ISBN 1—55581-246—5 (hardcover)
`
`1. Immunology. 2. Infection.
`[DNLM: 1. Immune System. 2. Immunity, Cellular. 3. Immunologic
`Diseases. 4. Infection. QW 504 I3 33 2004]
`I. Pier, Gerald Bryan. 11.
`Lyczak, Jeffrey B. III. Wetzler, Lee M. IV. Title.
`QRIS 1.1443 2004
`616.07’9—dc21
`
`2003002554
`
`10987654321
`
`All Rights Reserved
`Printed in the United States ofAmerica
`
`

`

`
`
`Cancer and the
`Immune System
`Lisa H. Butterfield, Stephen P. Schoenberger,
`and Iejj‘rey B. Lyczak
`
` topics covered
`
`
`A Genetic and physiological aspects of tumorigenesis
`
`A Immune recognition of tumors: tumor antigens
`
`
`
`
`A Immune cell types that respond to tumors
`
`A Cancer immunotherapies
`
`
`_' ancer can be considered as a disease resulting from the progressive cel-
`lular expansion of a single cell whose progeny have escaped from nor-
`mal regulatory mechanisms controlling cell division and homeostasis.
`
`7" At first glance, cancer appears to be a vast and bewildering array ofdis-
`eases, with as many different types of cancer as there are types of cells in the body
`[Table 24.1). There are, in fact, over 100 different types of cancer known, and
`subtypes of these disease states can be found within specific organs. As methods
`for the treatment and prevention of infectious and cardiovascular diseases im-
`prove, cancer is emerging as the leading cause of death in industrialized countries
`(Fig. 24.1). Although conventional cancer
`treatments such as surgery,
`chemotherapy, and radiation have greatly enhanced patient survival, manipula-
`tion of the immune response to cancer cells to promote their destruction remains
`an important and increasingly realistic goal for physicians. Immunological con-
`trol ofcancers could conceivably play a role in the eradication ofprimary tumors
`and disseminated metastases as well as the residual cancer cells that remain after
`conventional treatment regimens. The ideal result of immunotherapy would be
`the specific eradication of cancer cells with minimal damage to normal host cells.
`However, almost by definition a tumor cell has escaped immunologic recogni—
`tion and progressed to cancer because the affected patient’s immune system did
`not control tumor growth. Attainment of the goal of effective immunotherapy
`for tumors requires an understanding ofhow the immune system both fails to re~
`spond to cancer cells and has the potential to respond and the ways in which this
`response can be strategically manipulated.
`
`573
`
`

`

`Table 24.1 Nomenclature of several types of cancer
`Normal tissue
`Benign tumor“
`Blood vessels
`Angioma
`Bone
`Osteoma
`Cartilage
`Chondroma
`Epithelium
`Papilloma
`Glandular epithelium
`Adenoma
`
`Malignant tumor"
`Angiosarcoma
`Osteosarcoma
`Chondrosarcoma
`Carcinoma
`Adenocarcinoma
`
`Hepatocarcinoma
`Hepatorna
`Liver hepatocytes
`Rhabdomyosarcorna
`Rhabdomyoma
`Skeletal muscle
`
`Smooth muscle Leiomyosarcorna Leiomyoma
`
`“Benign tumors are anatomically restricted to their original tissue site.
`‘Malignant rumors are capable of spreading (metastasis) in distant sites.
`
`Figure 24.1 Cancer deaths in the United States, comparing the period from 1950 to 1969 with the period
`from 1970 to 1994. Data are for white males of all ages, are grouped according to county, and are expressed as
`the number of cancer-related deaths per 100,000 person-years. The vertical black bar in the center of each
`graph shows the nationwide average of cancer-related deaths. Data are from the National Cancer Institute’s
`Atlas of Cancer Mortality, which can be viewed at http:waw3.oancergovlatlasplusf.
`
`1950—1969
`
`1970—1994
`
`Abbeville, SC
`Acadia, LA
`Accomack, VA
`Ada, ID
`Adair, IA
`Adair, KY
`Adair, M0
`Adair, OK
`Adams, 00
`Adams, ID
`Adams, IL
`Adams. IN
`Adams, LA
`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
`Alleganv, MD
`Allegany, NY
`Alleghanv, NC
`Allegheny, VA
`Allegheny, PA
`Allen, IN
`Allen, KS
`Allen, KY '
`Allen, LA
`Allen, OH
`Allendale, 5C
`143.21
`
`
`
`Abbeville, SC
`Acadia, LA
`Accomack, VA
`Ada, ID
`Adair, IA
`Adair, KY
`Adair, MO
`Adair, OK
`Adams, C0
`Adams, ID
`Adams, IL
`Adams. IN
`Adams, [A
`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
`Allamaltee, LA
`Allegan, MI
`Allegany, MD
`Allegany, NY
`Alleghany, NC
`Allegheny, VA
`Allegheny. PA
`Allen, IN
`Allen, KS
`Allen, KY
`Allen, LA
`Allen, OH
`Allendale, SC
`
`
`
`574
`
`160.01
`
`176.31 + 192.6
`National average = 184.46
`
`203:5I
`
`225.2
`
`166.05
`
`183.42
`
`200.79 1 218.15
`National average = 209.47
`
`235.52
`
`252.89
`
`
`
`

`

`
`
`Cancer Is a Disease of Genes
`
`Through intensive research efforts over the past 25 years,
`cancer is now understood as a 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 which cells 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 rni—
`croenvironment (Fig. 24.2). Cancer arises 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. Exogenous factors,
`stimuli, or cues are shown in black type. Growth inhibitory factors
`and events are shown with red arrows. Growth stimulatory factors and
`events are shown with green arrows. TNF—R, tumor necrosis factor re—
`ceptor; CAM, cell adhesion molecule; FAK, focal adhesion kinase; RB,
`retinoblastoma tumor suppreSSor protein; TF. transcription factor.
`
`Neighboring
`
`
`
`Integrins,
`cadherins
`
`Growth arrest,
`
`migration arrest
`
`
`
`
`
` Growth factor
`
`Apoptosis
`
`
`
`
`
`receptor
`
`0 Growth factor
`
`Cancer and the Immune System
`
`575
`
`Mutations in
`' Growth factor
`receptor
`- Protein kinase
`
`Mutations in
`
`' Cell cycle regulators
`' Additional mutations
`
`- Loss of CAMS
`' Overproduction
`of matrix proteases
`
`o!oioto
`
`Normal
`cell
`
`Mutant,
`neOplastic cell
`{growth
`dysregulated,
`hyperproliferative)
`
`Benign tumor
`[genetically
`unstable)
`
`Malignant
`tumor
`(metastatic)
`
`Figure 24.3 The multistep process of tumorigenesis. The cell, which
`is originally normal (at the left), undergoes several genetic changes in
`a stepwise fashion. Each genetic change results in a phenotypic alter-
`ation that favors unregulated growth, exemption from apoptotic sig—
`nals, genetic instability, and metastasis (ability to spread from its origi—
`nal tissue site to other remote tissues of the host).
`
`cell undergoes a series of genetic alterations and acquires
`the capability to escape these regulatory mechanisms.
`This process is thought to occur in a discrete stepwise pro-
`cess involving the age—related incidence of four to seven
`stochastic events that drive the transformation of a nor-
`
`mal cell into highly malignant clonal derivatives (Fig.
`24.3). This process is similar to a Darwinian model of evo—
`lution, in that each genetic change confers a growth ad—
`vantage that leads to overrepresentation of the altered cell.
`The successive and heritable nature of cellular transfor—
`
`mation events is supported by histological analyses of pre—
`cancerous lesions revealing cells that appear to represent
`intermediate steps in the pathway between normal and
`transformed cells.
`
`Another known situation that establishes a genetic ba—
`sis for cancer comes from studies that have identified cer—
`
`tain mutant forms of normal genes that predispose indi—
`viduals to be at a greater risk for a given type of cancer. For
`example, women have a 10% lifetime risk for developing
`breast cancer, but among these patients are a small per—
`centage with mutations in one of two genes, BRCA1 and
`BRCA2, that greatly increase the risk of developing breast
`cancer. However, even carrying a high-risk mutation in
`the BRCA genes does not inevitably lead to breast cancer
`as 20 to 30% of women with mutant genes never deveIOp
`this disease. Thus there are clearly modifier genes that can
`counteract the negative effects of the mutant genes. Other
`genetic predispositions to cancer include colon cancer as-
`sociated with the adenomatous polyposis coli gene on
`chromosome 5; hereditary nonpolyposis colon cancer as-
`sociated with DNA mismatch repair genes on chromo-
`somes 2, 3, and 7; melanoma associated with the
`
`
`
`

`

`
`
`576
`
`Chapter 24
`
`CDNK2A gene on chromosome 9; testicular cancer asso—
`ciated with the TCGI gene on the X chromosome; and the
`Li-Fraumeni multiple cancer syndrome arising from mu—
`tations in the TP53 gene on chromosome 17.
`
`Genetic Changes in Transformed Cells
`Modern molecular biology has allowed the vast catalog 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 an—
`tonomous growth are numerous, certain molecular
`themes have become apparent, allowing these defects to
`be organized into classes, according to what growth-
`regulatory mechanism is affected (Table 24.2). Any defec-
`tive gene whose altered function promotes the conversion
`of a normal cell to a tumor cell is termed an oncogene. The
`normal version of the same gene is termed a proto-
`oncogene to denote that the gene is capable (through mu-
`tation) of giving rise 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 be loss of the gene’s original function, enhance—
`ment of its original function, or a change in the gene’s rate
`of transcription. In some cases, the prom-oncogene is 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.
`24.41%. In other cases, the proto-oncogene normally serves
`a role in preventing or delaying cell division, and a loss-of—
`function mutation in the oncogene removes this regula—
`tory mechanism, resulting in inappropriate cell division.
`Prom-oncogenes that fall into this category are sometimes
`referred to as rumor—suppressor genes or anti—oncogenes. An
`example of a tumor suppressor gene is the p53 protein,
`which normally functions to arrest the cell division cycle
`while DNA repair is proceeding, ensuring that existing
`
`mutations will be corrected and chromosomal integrity
`restored before DNA synthesis proceeds.
`Another way that tumor cells attain the ability to pro-
`liferate in an uncontrolled fashion is by becoming inde-
`pendent of the growth signals on which normal cells are
`dependent. Many ofthe oncogenes associated with cancer
`act by mimicking normal growth signals in various ways
`(Table 24.3). This can occur by increased expression of
`soluble growth factors or growth factor receptors that can
`lead to autocrine stimulation of cell division. Cancer cells
`
`often have alterations in the downstream cytoplasmic sig—
`naling components of growth factor receptors, leading to
`the constitutive transmission of growth signals, even in
`the absence of the actual growth factor. Examples of this
`type of change are the numerous point mutations found
`in res oncogenes that lead to their constitutive activation
`and the genetic translocations that lead to chronic myel-
`ogenous leukemia (CML). CML is due to a chromosome
`translocation known as t(9;22), which results from move-
`ment of the breakpoint cluster region (bet) on chromo-
`some 22 to the only! gene on chromosome 9. This translo-
`cation gives rise to what is known as the Philadelphia
`chromosome. The protein product of this fusion, the Abl
`tyrosine kinase, appears to be necessary for oncogenic
`transformation of CML cells. The wild—type c-Abl tyro-
`sine kinase does not transform cells. A major advance in
`cancer chemotherapy has recently occurred with the li~
`censing of 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 cancer cell’s growth program to be freed
`from its dependence on environmental signals does not in
`itself guarantee expansive growth. Work by Leonard
`Hayflick and colleagues in the 19605 revealed that cells in
`culture have a finite replicative potential and enter a non-
`proliferative “senescent” state after having achieved a cer-
`tain number of doublings (referred to in some older liter-
`ature as the “Hayfliclt number”). Cellular senescence can
`
`Table 24.2 Biochemical basis for stimulation of cell growth b oncogenes
`Prom-oncogene
`product
`c—Src"
`EGF—R
`
`Normal function of prom-oncogene
`Protein tyrosine kinase
`Growth factor receptor with intrinsic kinase activity
`
`Oncogene
`v-src“
`v-erbB
`
`v—sis
`
`PDGF
`
`Growth factor
`
`Alteration In oncogene
`Constitutively active
`Does not contain growth factor binding domain;
`kinase domain is constitutively active
`Overexpression
`
`Constitutively active
`Signaling molecule
`Ras
`Ha—ras
`Loss of inhibitory activity
`DNA—binding kinase; inhibitor of transcription
`Abl
`v-abl
`——__—_———_———————
`myc
`Myc
`Transcription factor
`Overexpression
`fl“v-” indicates a viral analog of the gene; “c-“ indicates a normal cellular version of the gene.
`
`____—_#-l
`
`

`

`
`
`Cancer and the Immune System
`
`577
`
`Ty'l‘ 52?
`src gene
`5’ -'—'I—I-l-—l—I.-Ill‘— 3’
`
`
`Substitulion of
`portion of src
`with viral
`genome
`
`
`
`
`5’
`
`
`
`src gene
`
`"1}":
`Chromosome Chromosome
`8
`14
`
`Point
`
`.
`mutation
`
`src gene
`
`Provirus
`
`Translocation
`
`Gln Tyr Gln
`CAG TAC CAG
`
`—-)-
`
`Gln Ser Gln
`CAG TCC GAG
`
`3’
`
`I
`
`myc—Ig
`
`Chromofome
`149+
`
`Chromosome
`
`A
`
`B
`
`C
`
`Figure 24.4 Conversion ofa normal
`proto-oncogene to a cancer-promot—
`.
`.
`ing oncogene can result from changes
`in expresslon of the prom-oncogene
`or from alterations in the activity of
`the protein encoded by the proto—
`oncogene. (A) The src proto—onco—
`gene encodes a protein tyrosine ki—
`nase. Point mutation at the 3' end of
`the gene results in loss of the tyrosine
`at position 527 (Tyrm) that is crucial
`
`enzymatic activity. The regulatory ty~
`rosine also can be lost by insertion of
`Viral DNA that Interrupts the src gene
`coding sequence prior to Tyrsn. In
`either case, the mutant form of the
`kinase is constitutively active. (B) The
`
`mycproto—oncogeneencodesatran-
`
`scription factor that helps regulate
`cell division and cell death. Chromo—
`somal translocation between the q
`arm of chromosome 8 and the q arm
`of chromosome 14 places the myc
`gene in the middle ofthe Ig heavy
`chain locus, enhancing transcription
`ofthe 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
`the mycprom-oncogene causes over-
`virus type 1 (HTLV—l) provirus near
`expression ofmyc, driven by strong
`enhancer elements in the viral 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 enhance transcription (3)
`from the nearb m c
`romoter (P.,,
`[yellow oval] ) by binding to the
`proviral LTR.
`
`3'
`
`%
`Tax
`/
`Tax.
`
`I
`my: gene
`G
` 5’
`
`”9"
`HTLV-l provirus
`
`2
`
`1
`
`-
`
`3
`
`be overcome by disabling anti-oncogenes such as p53 and
`pRB, thus allowing the cells to proceed through additional
`rounds of division. Because this dysreguiation uncouples
`cell division from the normal mechanisms of DNA repair,
`
`the progeny of these cells accumulate chromosomal ab-
`normalities. These cells can reach a state called “crisis,”
`which is characterized by the large—scale cell death and the
`rare emergence of an immortalized variant that acquires
`
`Table 24.3 Characteristics acquired during emergence of a tumor cell
` Characteristics
`Mechanism
`Growth signal independence
`Mimic normal signals via altered
`signaling components
`
`Release from antiproliferative signals
`Acquire blood supply
`
`Loss of function of regulatory proteins
`Activate local angiogenesis
`
`Genetic example(s) of mutations and
`effects of cell growth
`Src, Ras: constitutive signaling; Her-ZfNeu:
`initiates signal without ligand p53; RB: cell cycle
`proceeds despite DNA damage
`Fas: cell does not respond to pro—apoptotic signals
`Vascular endothelial growth factor
`Angiomodulin
`Plasminogen activator, matrix metalloproteinase
`Degrade extracellular matrix
`Integrins
`Downregulate cell adhesion molecules
`CD44, focal adhesion kinase
`Modification of cell adhesion apparatus
`————..-—..._._.—___._.—._—_—__—__——_______
`
`Spread to other anatomic sites (metastasis)
`
`
`
`

`

`.578
`
`Chapter 24
`
`
`
`the capacity for limitless replicative potential. The molec—
`ular basis for cellular immortalization in cancer cells is
`
`thought to be their ability to maintain the length of the
`structures called telemeres that are found at the ends of
`chromosomes. Telomeres consist of several thousand re—
`
`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 reduced in length to be—
`low a crucial threshold length, they can no longer protect
`the chromosomes from end—to—end fusions with other
`
`chromosomes, and this may underlie the many karyotypic
`aberrations associated with crisis. Telomeres are normally
`maintained by an enzyme called telnmerase, which cat-
`alyzes the addition ofhexanucleotide repeats to the ends of
`telomeric DNA. Telomerase is not expressed in senescent
`normal cells, but numerous tumor samples have been
`found to express this enzyme at high levels, suggesting that
`cancer cells exploit this enZyme for their own benefit.
`Liberated from cellular senescence and capable of au—
`tonomous proliferation, the growing tumor mass requires
`a supply of oxygen and nutrients to sustain its growth, a
`need which becomes progressively more urgent as the mass
`of the tumor increases. The process ofangiogenesis leads to
`the formation of blood vessels and capillaries within a tis-
`sue and is carefully regulated by counterbalancing negative
`and positive signals. Some ofthese signals are mediated by
`soluble factors interacting with their receptors that are able
`to either promote or inhibit blood vessel growth. Others in-
`volve the interaction of cellular proteases with integrin
`
`molecules as well as elements ofthe extracellular matrix and
`
`can mediate the mobility ofvascular endothelial cells. The
`ability ofsolid tumors to induce angiogenesis seems to stem
`from several factors (Fig. 24.5). First, the physical expan-
`sion of the tumor per se 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 cancer to activate the “angiogenic
`switch” from vascular quiescence to sustained angiogenesis
`appears to represent an important step in the tumorigenic
`process. The work of Iudah 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 control the
`bioavailabiliry 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 the rate at
`which they die. The removal of cells in vivo normally oc—
`curs through programmed cell 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 emerging as a key feature of can-
`cer, with mounting evidence coming from both animal
`studies and clinical human tumor biopsies. Studies with
`
`Figure 24.5 Solid tumors induce angiogenesis
`and direct new blood vessels to grow into the
`tumor, providing the tumor with nutrients and
`waste removal. Growing tumor masses stimu-
`late angiogenesis by causing local tissue injury
`[1), thus activating the thrombin cascade (2).
`Thrombin activates endothelial cells and
`platelets (3) to produce matrix metallopro—
`teases (MMPs), VEGF, and tiSSue factor (TF).
`VEGF directs growth and elongation of vascu-
`lar endothelium (4). MMPS dissolve extracellu—
`lar matrix (ECM) components to allow growth
`of new vascular endothelium (5). TF stimulates
`further production of thrombin, setting up a
`positive feedback loop (6). Some tumors se-
`crete VEGF to enhance this process (7).
`Reprinted from D. E. Richard et al., Oncogene
`20:1556—1562, 2001, with permission.
`
`Vascular endothelium
`
`
`
`® Compression and
`injury to local tissue
`
`
`
`

`

`
`
`Cancer and the Immune System
`
`579
`
`mice have revealed that apoptosis pathways can be inter—
`rupted in tumor cells at several levels. In some cases, the
`tumor cells lose expression of a surface receptor protein
`that normally receives signals 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) use to in-
`duce apoptosis of their targets. In other cases, the bio-
`chemical signaling pathway that mediates apoptosis is ei-
`ther disabled or dysregulated to favor survival of the
`tumor cell. In Burldtt’s lymphoma, a tumor derived from
`lymphocytes, the transformed cells overexpress the anti—
`apoptotic protein Bcl—2. These cells are highly resistant to
`several cytotoxic mechanisms.
`Most tumors arise by the neoplastic transformation of
`a cell in a solid tissue and are therefore initially confined
`to a discrete anatomical location. In many cases, however,
`cells from the tumor acquire the ability to detach from the
`tumor mass and invade adjacent tissues and distant sites
`in a process called metastasis. These distant colonies are
`called metastases or secondary rumors and account for over
`90% of human cancer deaths. Metastasis allows tumor
`cells to expand to new areas where nutrients and space are
`not limiting and frequently results in the growth oftumor
`masses in other tissues or organs whose normal fianction
`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 genes that
`tether a cell to its surroundings, such as integrins, tissue
`homing molecules, and extracellular proteases. Some—
`times the newly formed metastases can conscript normal
`host tissue into the metastatic process by utilizing factors
`they produce such as matrix-degrading proteases or
`growth factors to promote tumor growth.
`
`The Immune Re5ponse to Cancer
`
`It has been more than 100 years since Paul Ehrlich first
`suggested that tumors could be destroyed by immune
`mechanisms. On the basis of this proposition, scientists
`began studying the interaction between immune cells and
`tumors in hopes of amplifying antitumor immunity as a
`means of treating cancer. Early experimental studies of
`the immune response to tumors focused on the out—
`growth versus rejection of tumor fragments transplanted
`between outbred mice. Tumor rejection in these cases was
`thought to reveal the existence of tumor-specific antigens
`and suggested that the immune system could be used to
`control cancer. However, in the 1930s Peter Gorer showed
`that the rejection observed in these experiments was actu-
`ally directed against the dissimilar major histocompatibil-
`
`ity complex (MHC) antigens on the graft and could not be
`distinguished from tissue rejection in general. It was only
`when inbred strains of mice became available that critical
`investigation into the immunogenicity ofttunors could be
`undertaken. Tumors from one mouse would usually grow
`in a second mouse if the two mice were ofthe same strain
`and hence shared MI-IC antigens, since the tumor would
`be seen as “self tissue” by the genetically identical recipi-
`ent mouse (Fig. 24.6A). However, if the recipient mouse
`was of a different strain and MHC type than the donor
`mouse, the tumor would be rejected by the recipient
`mouse. In the 19405 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 rumor-specific
`antigens [TSASD that could invoke protective immunity
`and prevent vaccinated mice from acquiring the same
`type of tumor at a later time (Fig. 24.613). It was later
`shown that this protective immunity could be induced
`within an individual animal and, importantly, could be
`transferred from a vaccinated mouse to 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 tumor in that im—
`munization with a given tumor able to confer protection
`from challenge with the identical tumor could 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 19603 showed that some virally in—
`duced tumors express TSAs that are identical to those ex—
`pressed by other tumors induced by the same virus but are
`distinct from the TSAs expressed by tumors induced by
`other viruses. We now know that such virus—specific TSAs
`are actually products of the viral genome that are ex-
`pressed in every cell infected by a given virus. Target anti-
`gens have been identified at the molecular level for a vari-
`ety of tumors. The existence of tumor-specific antigens
`and their immunogenicity are key factors determining the
`usefulness of immunotherapy against any given tumor.
`
`Mechanisms of Antltumor Immunity
`Classes of Tumor Antigens
`The molecular identification of tumor antigens has pro—
`vided important insights into the immune response to can—
`cer and remains a key factor in the development of antitu—
`mor immunotherapies. Antigens that are unique to a
`tumor represent a molecular target that the immune system
`
`
`
`

`

`
`
`580
`
`Chapter 24
`
`Tumor excised
`
`¢\
`
`l
`
`A
`
`Strain A
`mouse with
`
`tumor
`
`StralnA %recrpient
`
`_
`
`StrainB
`
`recipient
`
`Tumor develops
`
`No tumor deveIOps
`
`B Strain A mouse 1
`with chemically
`l
`induced tumor X
`TumorX excised I
`
`Strain A mouse 2
`with chemically
`induced tumor Y
`
`A portion oftumor X
`
`:wed...-byirradiation
`
`i
`I TumorY excised
`
`. . .
`
`Killed tumor X cells
`used as vaccine
`
`Figure24.6 Useofinbredmousestrainstodemonstrate
`
`antigen—spec1fic immune protection against transplanted
`tumors. (A) A tumor transplanted from one mouse to an-
`other will usually grow in the recipient mouse if the donor
`and recipient mice are of the same strain, since the tumor
`will appear as self tissue to the immune system of the re—
`cipient. However, the transplanted tumor will always be
`rejected by the immune system of the recipient mouse if
`the donor and recipient are of different strains. (B) Chemm
`ically induced tumors sometimes express antigens that are
`the result ofmutagenesis and are unique to each tumor
`(TSAsl. Killing tumor X from mouse 1 allows it to be used
`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 tumor X. This pro-
`tection is antigen specific, since the vaccinated mouse is
`not protected from challenge with live cells from tumor Y.
`
`. . .
`
`Vaccinated mouse
`
`cells from tumor X
`
`challenged with live
`
`Strain A
`
`recipients/lg . :.I
`
`/Vaccinated 11101158
`challenged with live
`cells from tumor Y
`
`l
`i
`@{LA
`No tumor develops
`Tumor develops
`
`can use to recognize and specifically destroy a tumor. These
`antigens are classified according to their pattern of expres—
`sion on tumor cells and on normal, nontransformed cells.
`
`TSAS
`
`TSAs are the ideal antigenic targets for an immune—based
`cancer therapy. An immune response against such an anti—
`gen holds the promise of attacking the tumor while spar—
`ing normal, healthy cells. TSAs are formed anytime a pro-
`tein produced by the tumor cells is qualitatively altered so
`that the protein has a sequence unique to the tumor. One
`example of this would be a tumor cell protein produced
`from a gene harboring one or more point mutations. An-
`other example would be viral proteins in a virally induced
`tumor. Since cancer is characterized by genomic instabil-
`ity, it is not unlikely that a tumor cell will eventually begin
`to produce a gene product that is unlike any expressed by
`
`normal host cells. From the standpoint of antitumor im—
`munotherapy, TSAs are attractive because of their unique—
`ness. Even other cells that bear mutations in the same pro—
`tein as the tumor are extremely unlikely to bear the exact
`same mutations. This benefit, however, is also a liability.
`Since TSAs are unique to each newly arising tumor, it can-
`not be assumed that any one tumor expresses a therapeu-
`tically useful TSA, and so the presence ofTSAs must be de-
`termined on a 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 tumor cells. Leukemias
`and lymphomas are typical manifestations of lymphoid
`cell cancers. It has been possible to remove the tumor cells
`and make anti—idiotypic antibodies and CTLs against tu-
`mor—specific idiotopes and use these to treat the cancer.
`
`
`
`

`

`
`
`
`
`Cancer and the Immune System
`
`581
`
`However, as there are no other known cell types that pro—
`duce any type of surface epitope analogous to idio'topes, it
`is likely that targeting of these types of TSAs will be lim—
`ited to lymphoid cancers.
`
`TAAs
`
`In many cases, a tumor will possess no unique antigens
`that the host’s lymphocytes can recognize or 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 immune system on
`the basis of quantitative changes in their protein expres-
`sion profiles. These antigens are not tumor specific but are
`termed tumor—associated antigens (TAAs) (Table 24.4).
`Oncofizmi antigens are one prime example ofa TAA. These
`antigens are encoded by genes expressed during embryo—
`genesis and fetal development but are transcriptionally
`silent in the adult. These genes encode proteins that likely
`play a role in the rapid growth of embryonic cells and have
`been reactivated to perform the same function in the
`rapidly growing tumor. The most prominent group of on-
`cofetal antigens are known as the cancer—testis antigens be-
`cause in addition to being expressed by cancer cells, they
`are also expressed in the testis in normal males. Examples
`include the MAGE superfamily (made up of family mem-
`bers designated MACE—A, MAGE-B, MAGE~C, MAGE-D,
`and necdin) whose members were first described in
`melanoma but later 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-