Cancer Antigens

8/15/2019 Cancer Antigens

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C o m m e n t a r y

C a n c e r A n t ig e n s: I m m u n e R e c o g n i t io n o f S e l fand A l t e r ed S e l fBy Alan N Houghton

From Mem orial Sloan-Kettering Cancer Center and C ornell Universi ty Medical College Ne wYork 10021

A taci t a s sump t ion o f cance r imm uno logy has beenthat tum ors express non-se l f or " fore ign" ant igens . Th e

recen t i den ti f ica t ion o f a handfu l o f po ten t i a ll y im mun ogen iccancer ant igens shows tha t they are not t ru ly fore ign. Al th oug hthe bou nda ry b e twe en se l f and non - se l f i s no t we l l -def ined ,th is f ir s t loo k a t cancer ant igens f i ts more w i th a se lf /a l te redse l f pa rad igm than w i th t he non- se l f pa rad igm fo r an tigensrecognized in infec t ious d iseases .

Tumor-specif ic Ant ige ns in Ani m al ModelsThe exper imenta l foundat ion for cancer imm uno logy com es

la rge ly f rom s tud ie s o f imm une r e j ec tion o f chemica l ly - andUV rad ia t ion - induced tumors i n syngene ic mice . The an -t i gens de f ined in t hese mouse sys t ems a re po ten t , t umor-specif ic de terminants , recognized by C TL s tha t a re expressedby tum or ce ll s bu t no t b y no rm a l ceUs o r even by indepen-dent ly der ived tumo rs (1 , 2) . S tudies by Bo on and co-w orkershave p rov ided a mode l fo r t he o r ig in o f t umor- spec i f i c an -t igens, us ing the mo use P815 mastocytoma tu mo r (3-6) . Treat-me n t o f P815 cance r ce ll s i n v i t ro w i th a mu tagen was usedto genera te var iant cancer ce l l s , ca l led turn- , tha t fa i led top roduce tum ors because o f s timu la t ion o f s t rong C TL re -sponses . The mutagen genera ted s ingle nucleot ide muta t ionsin coding regions , a l te r ing sol i ta ry amino ac ids and crea t ingnew ant igens for a C T L response to a l tered se lf . The se s ingleamino ac id mu ta t ions p rov ided e i the r a new ep i tope fo r TC Rr e c o g n it i on o r a n e w a g r e t o p e fo r b in d i n g t o M H C m o l e -cules (3 , 4) . In e i ther case , epi tope or agre tope , the ant igenwas tum or speci fi c because i t was p re sen ted th rough M H Conly by the mu tagen ized ma l ignan t c lone . Th e de t e rminan t swere un ique to t he t umor, even thou gh the o r ig ina l, non -

muta t ed gene cou ld be ub iqu i tous ly exp res sed , p rov id ing as t ructura l bas is for tumor-speci f ic recogni t ion (3) .A s t r i k ing f ind ing was tha t immuniza t ion wi th mu tage -

nized turn- ce l l s could induce protec t ion agains t the pa-r en ta l t um or ceUs , even if the o r ig ina l t um or was a poor lyimm unogen ic , spon taneous tumo r (5 , 6 ). These expe r imen t sp rov ide a s t rong ind ica t ion tha t even appa ren tly we ak ly im-munogen ic cance r s can be r e j ec t ed by an immune r e sponseaf ter effec t ive imm uniz at ion . Thu s , a l l tum ors m ay have an-t i gens t ha t can be r ecogn ized by the immune sys t em, bu t

the immu nogen ic i ty o f these an tigens can va ry f rom po tan t igens i n chemica l ly i nduced tumors t o l ow inhe ren t munogen ic i ty i n spon taneous tumors .

Reco gn i t i on o f po in t m u ta t ion i s no t t he on ly mo de l t um or r e j ec t ion in t he P815 mode l . T wo C TL c lones agaP815 va r ian t s r eac ted w i th t he p rodu c t o f a gene , ca l led Ptha t w as comple t e ly i den ti ca l t o t he gene p re sen t i n no rt is sues o f the mo use (7 ) . The an t igen encod ed by P IA expressed no t on ly by P815 , bu t a l so by an un re l a t ed mcell l ine derived from the syn geneic mo use strain. This f inra ised the prospect tha t shared , non m utate d ant igens canrecogn ized by T cel ls on tumo rs o f t he s ame h i s to log ic t y

Recognit ion of Different ia t ion A nt igens on Hu m an Canc

A b ody o f da ta ove r t he pas t two decades has de t e rmitha t t he im mu ne r epe r to i r e o f pe rsons wi th cance r con tB and T ce l l s tha t recog nize ant igens expressed by autognu s cancer cells . Th us, tolerance to h um an cancer, i f i t exdoes not de le te the imm une reper to i re agains t the cancer The kno wn un ive rse o f imm unog en ic an t igens ( i.e ., de f iby s t ruc ture or sequence) on human cancers i s smal l , buexpan ding rapidly (Table 1) . In contras t to the c lass ica l mos tud ie s, t he hum an imm une sys t em appea rs t o r ecogn izet igens expressed by norm al t issues . Th e imm un e reper toto m elanom a is the m ost extensively characterized of any cain humans . T he serologica l analys is of hum an m elano m ashown that ant igens expressed on cancer ce l l s ref lec t d i fferent ia tion s ta te of the norma l ce l l coun terpar t (melacyte) a t the same s tage of d i fferent ia t ion (8) . Imm un e recni t ion o f melano cyte d i fferent ia t ion ant igens has been demstra ted for h igh aff in i ty IgG autoant ibodies agains t melan

(9) . This parad igm of d ifferent ia t ion an t igens i s no w berev is i ted based on r ecen t kno wledg e o f T ce ll recogn i to f human me lanom a . Th i s i s exempl i f ied by a r epo r t i n i s sue by Cou l i e e t a l . (10 ) and two r epo r t s by Kaw akamal. (11 , 12) descr ib ing an ant igen, ca l led M elan-A or mnom a an t igen r ecogn ized by T ce ll s 1 (M AR T-I ) , exp resby me lanom a , me lanocy te s , and p igmen ted r e t ina l ce ll s not o ther no rmal t issues . This m elanocyte d i fferentia t iont igen w as presented to C TL of a t leas t 11 d i fferent persth rough c l as s I MH CH L A - A 2 . 1mo lecules expressed by mela-

J. Exp. M ed. 9 The Rockefeller University Press ~ 0022-1007/94/07/0001/04 $2.00Volume 180 July 1994 1-4

Published July 1, 1994


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Tab le 1 . Antigens on Autologous H um an Cancers Recognized by Antibody or T Cell Responses

Tum or Normal t issueAntigen type expression Com men ts R f

Ant ibody g p 7 5 b r o w n M elanoma M elanocytes M elanosomal protein 1Gangliosides M elanoma Neuroectoderm - Carbohydrate antigens

GM 2, GD 2) derived t issuesMelanotransferrin Melanocytes,

other tissuesHER2/neu Epi the l ium

T cell

p53, nonmutant

T,Tn,sialylTn

MAGE-1,3

T yrosinase albinoM U C 1

Melan -A/MART-1

Melanoma

Breast

Breast

Breast

Melanoma, lung, andother cancers

MelanomaPancreas,

breastMelanoma

Most cel ls

Epithelium

Testes

MelanocytesEpithelium

Melanocytes

pMe117 si lver? Melanoma Melanocytes

Potential uniquedeterminant

Overexpressed on aproport ion of cancers

No recognit ion ofmutant p53

Carbohydrate antigens

Not expressed bymelanocytes

Melanosomal proteinNon-MHC restr icted

Melanocytes and retina

Melanosomal protein

21

22

23

20

17181224

910111415

Antigens with kno wn structures that are recognized on autologous tumor cells.R , reference number.

nom a 10-12) . This defines a t rue shared tum or an t igen , ex-p r e ssed by t umo r s i n d i ff e r en t hos t s and r ec og n i z ed b y mo r ethan one pa t ien t .

The Me lan -A an t i gen i s now the fou r t h a u t oa n t i g e n onhum an me lanom a tha t i s spec if ica lly expressed by normal mel -anocy te s . CTL c lones o f one o f t he pa ti en t s w h o r e s po n dedto M e lan -A a l so r ecogn i zed ano the r no rm a l m e l an o c y te co n -s t i tuent , ty ros inase , presented by HL A- A2 .1 10 , 13). Thispa t ien t d id not have over t s igns of au to imm uni ty e .g ., depig-men ta t ion) and ye t had an ex t raord inar i ly go od c l inical coursea f te r mu l t i p l e r e s ec t ions o f me t a s ta t i c me l a n om a . A l tho u ghone canno t gene ral i ze t oo mu ch f rom a s ing l e p a ti en t , c l u e soften arise from these case studies. In this case, the clue istha t immune responses to res t r ic ted melanocyte d i ffe rent ia -t ion an t igens mig ht prevent progress ion of the cancer.

The i den t i t y and ce l lu l a r loca l iz a t ion o f M e lan -A r e ma i nsu n k n o w n . H o w e v e r , th r e e o th e r a u t o a n ti g e n s o n m e l a n o m aa re t r an smem brane g lycop ro t e in s exp re s s e d w i th in m e l ano -somes , the melanocyte-spec i f ic organel le tha t i s the s i te ofmelanin syn thes is . The se a re tyros inase the produc t of thec or albinol o cus ), gp75 t he p roduc t o f thebrownlocus) , andg p l 0 0 m a p p i n g n e a r o r w i t h i n t h esilverlocus) 9, 13-15).A pept ide wi th in gpl00 def ines another shared ep i tope , rec-ogn i zed by CT L f rom n ine me lanom a pa ti e n t s 1 4 - 1 6 ). I ti s wo r th poin t ing out tha t each of these products i s the hum an

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ho m ol ogu e o f a gen e o r g e ne t i c r eg io n t h a t de t e rmines coc o l o r in t h e m o use . W h y m e lan oso ma l g l ycop ro t ein s a re r e ad il y r e c og n i z e d by t he im m un e sy s tem r ema ins a mys t e r

An o th e r m od e l f o r r e co gn i t ion o f s e l f mo lecu l e s is exempl i f ied by the M AG E-1 and MA GE -3 ant igens systems 118 ). MA G E- 1 an d - 3 a re exp re sse d o n m e l anoma and o thtu m or t yp e s ) , b u t n o t o n no rm a l m e l a n ocy t es o r mo s t o thnormal t i s sues . In normal t i s sues , MAGE-1 and -3 appeato be res tr ic ted to the tes tes 17 , 18). Al th oug h the exac t cetype in the tes tes i s no t ye t identi f ied , the M AG E genes coub e r egu l a t e d d u r in g sp e rm a tog e nes i s o r e a r l y deve lopmeand then remain s i len t except a f te r mal ign ant t ransform at ion) . D iscover ing the func t ions of these genes wi l l p rovifur ther ins ights .

There a re severa l po in ts to make about th i s universe o

hu m an ca ncer antigens Table 1) . First , these studies are a n ea rl y s tag e , and t h e ma j o r i t y o f w or k i n human canct o d a t e ha s been do ne i n me l an om a . I t w o u ld be p r ema tu rto generalize to al l cancers at this point . Second, the majorio f an t ig e ns r eco gn i ze d b y t he i mm u n e s y s tem i s exp re ssebot h by the mal ignan t ce l l and norma l cel l coun terpar t e .gmelanoma and melanocyte) , and therefore represents an app a ren t au to im m un e r e c og n i t io n . Th i r d , t h e ev idence t o dareflec ts im m une reper to i re , i .e ., i t is no t ye t poss ib le to knowh ethe r T ce l l o r an t ibod y responses t ru ly represent im mu n



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re jec tion of cancer. D is t inguishing im mu ne reper to i re f roma protective im mu ne response in vivo and in si tu w ill be crit-ical . Evidence for high t i ter, hig h affinity IgG antib ody re-sponses or hig h precu rsor frequencies of T cells is cons istentwith a specific immune response to the tumor in vivo, buti t is possible that these responses are not to the tumor butto t i ssue in jury or some other event in the hos t .

If self proteins of hu ma n cancer can be recognized by C TLs,can T cells recog nize muta tion s, for instanceras , p53 ,or o theraltered alleles? Muta tions inras and p 5 3 a re no t com mon inhum an melano ma, and i t is too early to kn ow the f requencyof imm une reco gni t ion of these muta t ions in o ther cancers.These are certainly attractive targets. How ever, wh eth er theseare realistic epitopes for the immune response is uncertain.Evidence points to the l ikelihood that there are T cells inthe immune reper to i re tha t can recognize mutantras pep-tides 19). Yet i t is possible t hat m any mu tation s are notpresented to the imm une system on M H C molecules of hum ancancer cells. Presentation would require appropriate processingand t r im min g of pept ides , t ranspor t to the correc t compar t -ment for MHC binding, and express ion of an appropr ia te

M H C allele tha t could accept the pept ide . I f s t rongly im-mun ogenic m uta t ions were presented by the tum or, c lonescould be des t royed by an im mu ne response , b ut surv iv ingtum or c lones could avoid the response b y mu ta t ion or down -regula t ion of the gene encoding the pept ide , or by down-regulation of M H C , peptide transporter, or othe r escape routes.

In part icular, i f the mu tatio n is no t crucial to m aintain ingthe ma l ignant or m etas ta t ic phenotype , then subclones n otexpressing the mutant peptide might readily survive.

Mu ta t ions appear to accumula te progressive ly in h uma ncancers, particu larly durin g later stages of tum or progression.In con trast, chemically induc ed tum ors acquire a large numb erof muta t ion s s imul taneous ly at an ear ly s tage of tu mo r de-velopment . The expression of potent unique tum or re jec t ionantigens in chem ically induc ed tum ors ma y reflect the acqui-s i t ion o f a la rge nu mber of muta t ions ear ly in tum or progres-sion, allow ing less chance for selection by th e im m un e systemand provid ing a s tochas t ic model for recogni t ion of theseunique antigens.

F i n a l C o m m e n t s

Hu ma n studies of imm un e responses to cancer have shownthat norm al d i fferent ia t ion ant igens are recognized by thehost . In this respect, tu m or im mu no log y shares com mo n features wi th the s tudy of au to imm une d isease . Both f ie lds areconcerned wit h the im mu ne response to cellular antigens andthe role of this response in the pathogen esis of disease. How -ever, the therapeut ic goals of tumor im m un ol og y- to induceor au gmen t the imm une response agains t transformed ce l l s -are the opposite of those for au toim mu ne diseases. Explora-t ion of the imm une reper to i re against hum an cancer poin tsto restr icted differentiat ion antigens as a start ing point forunderstanding the antigens recognized on cancer cells .

Address correspondence o Dr. A lan N. Hou ghton, Clinical Imm unology Service, Mem orial Sloan-KettCancer Center,1275York Avenue, New York, NY 10021.

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3 oughton



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Cancer Antigens

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