[CANCER RESEARCH 50, 8023-8027, December 15, 1990]

Reduced Expression of HLA Class I and II Antigens in Colon Cancer1

Carl J. McDougall, Sing Shang Ngoi, Ira S. Goldman, Thomas Godwin, Juan Felix, Jerome J. DeCosse, andBasil Rigas2

Departments of Medicine, Surgery and Pathology, Cornell University Medical College, New York, New York 10021 {C. J .M., S. S. N., T. G., J. F., J. J. D., B. K.J, andDepartment of Medicine, North Shore University Hospital-Cornell University Medical College, Manhasset, New York 11030 [1. S. G.J

ABSTRACT

The expression of HLA class I and II antigens was studied byinuminoli istnchcmistry in (a) specimens of colon cancer from 25 patients,(b) normal colonie mucosa obtained 5-10 cm away from each tumor, and(e) colonie mucosa from 13 normal individuals. Thirteen of the tumorspecimens had normal epithelium adjacent to the cancer, which thusserved as an internal control.

The expression of HLA class I antigens in colon cancer was dramatically reduced compared to control (/' < 0.0001): undetectable in 28%,

diminished in 68%, normal in 4%. The expression of class II antigenswas also reduced in cancer (P < 0.0001 for all when compared to normal),being undetectable in most (HLA-DP 64%, HLA-DQ 72%, HLA-DR68%). In 44% of the cancers all three HLA class II antigens wereundetectable; in 92% at least one class II antigen was undetectable; andin 20% both class I and class II antigens were undetectable. No cancerspecimen had a completely normal HLA phenotype. The expression ofother surface antigens was preserved in cancer tissues and, therefore,loss of HLA antigens was not due to a nonspecific decline in surfacemolecules.

When glands of normal mucosa immediately adjacent to cancer werecompared to those of normal controls, significantly reduced expressionof only HLA class I antigens (P = 0.0149) and HLA-DP (P = 0.034)was found. The expression of the HLA antigens in colonie mucosa remotefrom the cancer was no different from that of normal controls.

Our data show extensive and significant reduction in the expression ofHLA antigens in colon cancer; its potential relationship to immunosur-veillance in cancer is discussed.

INTRODUCTION

The development of malignant tumors represents not onlyneoplastia transformation but also the failure of host resistanceto eliminate aberrant cells. Because neoplastic cells frequentlyexpress surface antigens (neoantigens), they are recognized asforeign and eliminated by the host. Effective immunosurveil-lance requires not only an immunocompetent host but alsoexpression of MHC3 class I antigens along with tumor neoan

tigens.The MHC, referred to as HLA in man (1), encodes three

classes of gene products: class I, these are major determinantsof graft rejection and serve as self-recognition elements forcytotoxic T-cells; class II, these function in antigen presentationand in self-recognition by helper T-cells; class III, these arecomponents of the complement system. Altered expression ofMHC antigens has been proposed as a mechanism which protects tumor cells from immunosurveillance (2-5). The basicpremise concerning the role of class I molecules in oncogenesis

Received 12/11/89; accepted 9/17/90.The costs of publication of this article were defrayed in part by the payment

of page charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1This work was supported in part by a gift to B. R. from the Wendy Will Case

Cancer Fund and from the Cancer Prevention Research Fund at The New YorkHospital.

1To whom requests for reprints should be addressed, at Division of DigestiveDiseases, The New York Hospital, F-231, 525 East 68th Street, New York, NY10021.

3The abbreviations used are: MHC, major histocompatibility complex; PBS,phosphate-buffered saline; CEA, carcinoembryonic antigen; EMA, epithelialmembrane antigen.

is that, since they are required in the presentation of neoantigens on tumor cells to the cytotoxic T-lymphocytes, theirabsence from the cell surface may lead to escape of these tumorsfrom immunosurveillance. Experimental evidence supports thisconcept (4, 6, 7). For example, transformation of cells byadenovirus type 12 is associated with reduced expression ofMHC class I antigens and increased tumorigenicity in syngeneicimmunocompetent hosts. Expression of transfected MHC classI genes in the adenovirus type 12-transformed cells can abrogatetheir tumorigenicity.

Although the expression of HLA antigens in colon tumorshas been investigated recently (8-12), the data are both conflicting and fragmented. The expression of MHC class I and IIantigens in the same tissue sample and with appropriate controls has not been studied. In this paper we report the resultsof our comprehensive study of the expression of HLA antigensin colon cancer, in normal mucosa from the same individualobtained at a distance from the cancer, and in normal coloniemucosa from persons with no evidence of colonie neoplasia ordisease.

MATERIALS AND METHODS

Patients and Tissues

Twenty-five unselected patients undergoing surgery at New YorkHospital-Cornell Medical Center or North Shore University Hospital-Cornell Medical Center for removal of colon cancer between January1988 and June 1989 were studied. There were 16 men and 9 women.The average age was 69 years; the range was 42-92 years. All hadhistological verification of colon cancer. When staged according to theAstler-Coller modification of the Dukes' system, 16% of the tumors

were B,, 32% B2, 24% C,%, and 28% C2. Demographic features ofpatients and control subjects are included in Tables 1 and 2. All cancerswere moderately well differentiated and in none did a mucinous component predominate.

As soon as the operative specimen was available paired samples ofcancer and nonneoplastic mucosa were obtained 5-10 cm away fromthe tumor. The tissue was embedded in Optimal Cutting Temperaturecompound (Miles Scientific, Naperville, IL), frozen immediately inisopentane cooled in liquid nitrogen, and stored at -70°Cuntil used.

Thirteen normal subjects served as controls. Eight were men and 5were women; their average age was 57 years (range, 38-75 years). Theseindividuals, evaluated between January 1988 and June 1989, had normal colonoscopy findings and no personal or family history of colonieneoplasia. Colonie tissue, obtained by biopsy during endoscopy, wasprocessed in the same manner as the surgical specimens. Thirteencancer specimens consisted of both normal and malignant tissue. Thespecimens obtained at a distance from the tumor as well as thoseobtained from subjects with no apparent colonie disease were histolog-ically normal.

The study was approved by the appropriate Committees for HumanRights in Research.

Immunohistochemistry for HLA Antigens

Four-/¿mtissue sections mounted on pretreated microscope slideswere stained by indirect immunoperoxidase. Briefly, after equilibrationto room temperature for 30 min, samples were fixed in acetone for 5

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HLA EXPRESSION IN COLON CANCER

min and then incubated for 15 min in 0.9% H2O2 in methanol. Rehy-dration was accomplished by three washes in 95% alcohol followed bywater, before transferring the specimens to PBS. A 30-min incubationin horse serum (Vector Laboratories, Burlingame, CA) diluted 1:10 inPBS containing 2% bovine serum albumin (Sigma Chemical Co.) wasfollowed by addition of the primary monoclonal antibody. The sampleswere then incubated in a humidified chamber overnight at 4°C.This

was followed by incubation with the secondary biotinylated antibody(horse anti-mouse) for 60 min. The avidin-peroxidase complex (VectorLaboratories) was added for 30 min, followed by the addition of 3,3'-

diaminobenzidine tetrachloride (grade II; Sigma), the final coloringagent. Between each antibody treatment the slides were washed threetimes with PBS. Tissue was counterstained with hematoxylin andexamined under the microscope.

Antibodies. The following monoclonal antibodies were used: for HLAclass I antigens, clone W6/32 (IgG2a) which recognizes shared determinants of HLA-A, -B, and -C (Sera-lab, Westbury, NY); for HLA-DP, clone B7/21 (IgGl; Becton Dickinson, Mountain View, CA) whichrecognizes a monomorphic epitope on DP molecules; for HLA-DQ,clone SK10 (IgGl; Becton Dickinson) which recognizes a polymorphicepitope on DQ molecules; for HLA-DR, clone L243 (IgG2a; BectonDickinson) which recognizes a nonpolymorphic HLA-DR epitope anddoes not cross-react with DQ or DP; for CEA, an IgGl monoclonalantibody which recognizes a polymorphic CEA epitope (Dako Corp.,Carpintería,CA); for EMA, clone E29 (IgGl; Dako) which recognizesa monomorphic epitope on EMA.

Controls. Positive control: for HLA class I antigens, normal colon;for class II, human tonsil. Negative control: nonspecific immunoglob-ulin of the same class and subclass as the primary antibody (BectonDickinson) and at the same concentration. To minimize intraassayvariability, sections of tumor, histologically normal mucosa from thesame patient, and positive control tissue were processed on the samemicroscope slide. Additional control: the expression of CEA and EMAwas assessed as control of the expression of cell surface molecules.

Evaluation. Samples were rated blindly by two pathologists (J. F., T.G.) according to the following scale: 4+, all glands stain strongly, i.e..as strongly as normal control tissue processed simultaneously; 3+, allglands stain less than maximally without being "trace" (category 1+)

or >75% of the cells stain; 2+, between 25 and 75% of tumor cellsstain; 1+, <25% of the cells stain or trace staining of all or most cells;0, no glands stain positively.

Statistical Methods

The Fisher exact test was used to compare the frequency of expression of HLA antigens in the various groups of samples that we studied.

RESULTS

Class I Antigens. Tables 1 and 2 and Fig. 1 present the resultsobtained from the colon cancers and the control tissues. Theexpression of HLA class I antigens was uniformly 4+ in thenormal subjects. In the malignant cells, the expression of HLA

Table 1 HLA expression in normal individuals

Patientage(yr)/sex38/M40/M75/M45/F55/M74/M62/F48/M56/M63/F40/M70/M70/MClassI4+°4+4+4+4+4+4+4+4+4+4+4+4+DP4+2+3+4+4+2+3+3+4+4+3+4+3+Class

IIDQ4+2+3+4+3+3+3+4+4+3+3+4+1+DR2+1+1+3+1+2+1

+3+3+2+2+3+0+

" Immunoperoxidase scoring as in "Materials and Methods."

class I antigens was dramatically reduced: in 28% of the samplesit was not detectable, in 60% it was diminished (1+ to 3+), andin 4% it was present at levels noted in normal subjects. Compared to normal control tissue this difference was highly significant (P < 0.0001). The expression of HLA class I antigens incolon cancer was significantly reduced (P < 0.0001) comparedboth to its immediately adjacent mucosa (P < 0.0001) and toremote mucosa (P < 0.004). The histologically normal mucosaremote from colon cancer displayed these antigens maximally(4+) in 84% of the patients, whereas in 16% their expressionwas reduced (3+); this difference, however, was not statisticallysignificant (P = 0.696). The expression of HLA class I antigensin histologically normal mucosa immediately adjacent to cancerwas reduced compared to normal mucosa (P = 0.0149) but didnot differ significantly from that of remote colonie mucosa (P= 0.0967). Fig. 2, a-c, displays a typical example of alteredexpression of HLA class I antigens in colon cancer.

Class II Antigens. Colonie epithelium from all normal subjects expressed the three HLA class II loci with the exceptionof a sample from one individual who did not have detectableHLA-DR antigens (Table 1). In the majority of these subjectsthe intensity of the expression of MHC class II antigens wasbetween 2+ and 3+. No cases stained maximally (4+) for HLA-DR. The expression of the three class II loci appeared to benoncoordinate, i.e., the antigen density of one class II locus wasnot necessarily the same as either of the remaining class II loci.

The expression of HLA class II antigens was dramaticallyreduced in the malignant tissue (Table 2). Neoplastic colonieepithelial cells from the majority of the patients failed to expressdetectable amounts of HLA class II antigens (HLA-DP, 64%;HLA-DQ, 72%; HLA-DR, 68%). In 44% of the cancers allthree HLA class II antigens were undetectable, whereas 92% ofthem had complete loss of expression of at least one HLA classII antigen.

Compared to normal mucosa, the expression of HLA-DPwas significantly reduced in colon cancer (P< 0.0001) and alsoin normal mucosa immediately adjacent to cancer (P < 0.002);it was, however, no different from that in histologically normalmucosa remote from the tumor. The reduction in the expressionof HLA-DP was more pronounced in colon cancer than in theadjacent normal mucosa; the difference between the two wasstatistically significant (P < 0.0005).

The expression of both HLA-DQ and -DR, when comparedto normal mucosa, was significantly reduced in colon cancer (P< 0.0001) but not in the normal mucosa immediately adjacentto cancer or the normal mucosa remote from cancer. Theexpression of these antigens in colon cancer was also reducedwhen compared to the normal mucosa either immediately adjacent to cancer (P < 0.0002) or remote from it (P < 0.0001).

Fig. 2, d-f, shows an example of altered expression of HLAclass II antigens in colon cancer. Fig. 1 summarizes the resultson the expression of HLA class I and II antigens in all groupsof colonie tissue that we studied. It is of interest that 20% ofthe cancers showed complete loss of both HLA class I and IIantigens and none of the cancer specimens had a completelynormal HLA phenotype.

For both Class I and II antigens positive staining in thenormal colonie glands was seen throughout the gland (upperand lower crypt) and was mainly in goblet cells. Staining wasless along the surface where columnar cells predominate. WhenHLA expression was detectable in cancer, there was usuallyheterogeneity of expression between glands on the same specimen. All of the cancers were moderately well differentiated,

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HLA EXPRESSION IN COLON CANCER

Table 2 HLA expression in colon cancer

Patientage(yr)/sex°82/F62/F82/M56/M81/F42/F71/F70/F58/M66/M70/M77/M52/F84/F74/M70/M82/M57/M72/M68/M70/M82/M58/M92/F62/MDukes'stageB2c,B,B!B,B,B,B,C,B,C,B,B,C,B,C,c,B,C,c,C2c,C2C,c,RN*4+4+4+2+4+4+4+4+4+4+4+4+4+4+4+4+4+3+4+4+3+4+3+4+4+Class

IAN4+4+2+4+4+4+3+3+3+4+3+3+4+C0+1+2+0+0+1+1+3+2+3+1+1+1+1+1+0+1+2+0+0+0+2+0+1+4+RN2+2+1+0+0+4+4+3+2+4+4+4+3+2+3+2+2+1+2+2+3+3+0+0+4+DPAN3+2+2+2+2+1+1+1+3+3+0+1+4+C0+0+0+0+0+i+i+i+2+0+1+0+3+1+0+0+0

+0+0+0+0+0+0+1+0+RN3+2+1+3+1+4+3+2+3+3+3+4+3+3+4+2+2+1+1+2+1+2+1+3+4+Class

IIDQAN3+3+2+3+2+1+1+1+1+2+1+0+4+C0+0+0+0+0+1+1+0+2+1+0+0+1+0+IH0+0+0+0+4+1+0+0+0+0+RN3+1+1+3+4+4+2+3+3+2+1+3+3+4+4+3+2+1+2+2+0+2+1+3+3+DRAN3+4+3+3+1+1+1+1+0+2+1+0+3+C0+2+0+0+0+0+0+1+2+1

+0+0+i+i+0+0+2+0+0+0+0+0+0+0+0+

"n = 25.* RN, remote normal: histologically normal colonie mucosa 5-10 cm away from the tumor; AN, adjacent normal: histologically normal colonie mucosa seen on

the same tissue section with cancer and in continuity with it; C, cancer. Immunoperoxidase scoring as in "Materials and Methods."

CO

Normal from cancer patients

100

80

60

40

20

Cancer HLA Class IHLA - DP

HLA - DQ

HLA-DR

2+ 3+

HLA Expression ScoreFig. 1. HLA antigen expression in colon tissues. The expression of HLA

antigens was studied in colon tissue obtained from normal individuals (top), fromcolon carcinomas (bottom), and from apparently normal mucosa 5-10 cm fromeach cancer studied (middle). Columns, percentages of subjects in each grouphaving the corresponding immunoperoxidase score; the scoring system is definedin the text.

suggesting that there was no correlation between HLA expression and degree of histological differentiation. Similarly, nocorrelation between HLA expression and Dukes' stage was

detected.8025

Surface Antigens. In order to determine the specificity of theobserved changes in HLA antigen expression, the expressionof CEA and EM A was determined in a subset of six tissue pairs(cancer and normal mucosa 5-10 cm from the cancer) in whichthe tumors showed reduced HLA antigen expression. In allcases, in the cancer tissue the expression of CEA and EM A waseither the same or slightly increased compared to the corresponding normal tissue.

DISCUSSION

Our data demonstrate a profound reduction in the expressionof both HLA class I and II antigens in colonie carcinomas, ascompared to three control tissues, namely,normal colon, mucosa remote from the cancer (5-10 cm away from the tumor),and normal mucosa immediately adjacent to cancer. All cancerspecimens examined displayed some abnormality in the expression of HLA antigens, and, in general, these abnormalities wereextensive. The normal expression of CEA and EMA, two cellsurface antigens, in tumors with loss of HLA antigens suggeststhat this is a specific change and not one due to a generalized,nonspecific mechanism of MHC down-regulation or an artifactdue to a blocking factor.

Our findings are in agreement with some of the previouslyreported work in this area. Reduction in the expression of HLAclass I antigens in colon cancer has been observed, although itsreported incidence varies widely between 10 and 100% (8-12).On the other hand, HLA class II antigens have been reportedas appearing de novo in colon cancer on the assumption thatnormal colonie tissues do not express these antigens (9, 10).Because of these discrepancies, the following points merit briefdiscussion.

First, from a technical standpoint it should be emphasizedthat in our study (a) all tissue samples were obtained and frozenin liquid nitrogen immediately after their removal, (b) each pairof tissue samples (colon cancer and tissue remote from the

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HLA EXPRESSION IN COLON CANCER

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Fig. 2. Immunohistochemistry of HLA antigens in colon tissues, a, normal colon displaying class I antigens (inset, negative control, x 100), A, colon cancershowing no expression of class I antigens, c, carcinoma adjacent to normal glands (the normal portion displays class I antigens but the malignant does not); d-f, samesequence and findings for class II antigens; d, inset, negative control, a-e, x 200; / x 400.

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HLA EXPRESSION IN COLON CANCER

cancer) was processed on the same microscope slide, (c) anegative and a positive control for immunoperoxidase wasalways included, (d) colonie tissues from normal subjects wereexamined using the same antibodies as for tissues from patientswith colon cancer, and (e) in the 13 cases in which normal andmalignant colonie tissue coexisted on a microtome section, theimmunohistochemical patterns of these two areas of the tissuewere appropriately different. The latter was a valuable internalcontrol.

Second, although some authors report that class II antigensare not normally present in colonie epithelium, others havefound just the opposite (13). The work of Mayer and and Shlien(14) has provided not only descriptive but also functional evidence of the expression of HLA class II antigens in colonieepithelium. Our findings in entirely normal colon tissues agreewith those of the latter groups of investigators. Our studydocuments that the expression of HLA class II antigens can bevery different in normal mucosa obtained from normal subjectsand histologically normal mucosa from patients with coloncancer. The abnormality in the expression of HLA class IIantigens that we observed should, therefore, be considered as areduced expression of HLA class II antigens in colon cancer.

Since we measured the composite expression of HLA class Iantigens we cannot evaluate the contribution of individual locito the final result. However, in the cases showing no class Iactivity, one can assume that either extensive abnormalities inthe regulation of the three class I loci (A, B, and C) occurredor substantial chromosomal damage took place in the shortarm of chromosome 6, where the HLA gene complex resides.Alternatively, lack of expression of fo-microglobulin, which isrequired for insertion of class I antigens into cell membranes,may have taken place (11). Current evidence from other systemssuggests that oncogenes may down-regulate the expression of

HLA class I antigens (IS, 16). Oncogene activation in coloncancer is amply documented (17), but whether it has any effecton HLA expression is unknown.

The hypothesis has been advanced that tumor cells not expressing these antigens succeed in becoming an overt tumor bynot presenting their tumor antigens to cytotoxic lymphocytes,which would otherwise eliminate them. Although this is anattractive concept, there is no direct proof of it (2, 4). Furthermore, it is unknown whether such mechanisms are at all operative in colonie carcinogenesis. Recent evidence suggests thatloss of MHC class I antigens from cells that constitutivelyexpress them may provide tumorigenic properties that go beyond escaping immunosurveillance and, in some cases, may beclosely linked to the process of malignant transformation (18).

The expression of HLA class I antigens in mucosa remotefrom the tumor was reduced in some cases, but this differencedid not reach statistical significance. On the other hand, theexpression of HLA class I and HLA-DP antigens in normalmucosa immediately adjacent to cancer, when compared to thatof normal controls, was significantly reduced. Although somecaution is required in evaluating these findings (the significancelevels for these two results were not extremely small), thepossibility of incipient changes in HLA expression even beforehistologically overt abnormalities become apparent has to beconsidered.

Lack of expression of all three HLA class II antigens occurredin 44% of the patients. The expression of individual HLA classII antigens was completely lost in between 64 and 72% of

cancer patients. That these numbers are substantially higherthan the 28% frequency of complete loss of HLA class Iantigens is explained by the fact that the latter determines theproduct of three loci. Until the regulation of the expression ofthese antigens is better understood, it is, however, rather difficult to speculate on the underlying mechanisms.

In summary, our data indicate extensive and significant reduction in the expression of class I and II antigens in coloncancer to the point that no cancer sample examined had anormal HLA phenotype.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the statistical analysis of thedata by Dr. M. L. Lesser, advice from Dr. P. Garin-Chesa, technicalassistance from Anna Maria Giabruno and Christopher Lovelace, andassistance in manuscript preparation from Murray Cohen.

REFERENCES

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2. Tanaka, K., Yoshioka, T., Bierberich. C., and Jay, G. Role of major histo-compatibility complex class I antigens in tumor growth and metastasis. Annu.Rev. lmnimm!., 6: 359-380, 1986.

3. Hammerling, G. J., Klar, D., Pulm, W., Momburg, F., and Moldenhauer, G.The influence of major histocompatibility complex class I antigens on tumorgrowth and metastasis. Biochim. Biophys. Acta, 907: 245-259, 1987.

4. Tanaka, K.. Isselbacher, K. J.. Khoury, G. and Jay, G. Reversal of oncogenesisby the expression of a major histocompatibilty complex class I gene. Science(Washington DC), 22«:26-31, 1983.

5. Goodnow, R. S., Vogel, J. M.. and Linsk, R. L. Histocompatibility antigenson murine tumors. Science (Washington DC), 230: 777-785, 1985.

6. Bernards. R., Schrier, P. I., Houweling. A.. Bos, J. L., van der Eb, A. J.,Zijistra, M., and Melief, C. J. M. Tumorigenicity of cells transformed byadenovirus type 12 by evasion of T-cell immunity. Nature (Lond.). 305: 776-779, 1983.

7. Schier, P. 1., Bernards, R., Vaessen, R. T. M. J., Houweling, A., and van derEb, A. J. Expression of class I major histocompatibility antigens switchedoff by highly oncogenic adenovirus 12 in transformed rat cells. Nature(Lond.), 305: 771-775, 1983.

8. van den Ingh, H. T., Ruiter, D. J., Griffioen, J., van Muijen, G. N. P., andFerrone. S.. HLA antigens in colorectal tumors—low expression of HLAclass I antigens in mucinous colorectal carcinomas. Br. J. Cancer, 55: 125-130, 1987.

9. Momburg. F.. Degener, T., Bacchus, E., Moldenhauer, G.. Hammerling, G.J., and Moller, P. Loss of HLA-A.B.C and de novo expression of HLA-D incolorectal cancer. Int. J. Cancer, 37: 179-184. 1986.

10. Degener, T., Momburg, F., and Moeller, P. Differential expression of HLA-DR, HLA-DP, HLA-DQ and associated invariant chain (li) in colorectalmucosa, adenoma, and carcinoma. Virchows Arch. Pathol. Anat. Histo-pathol., 4/2:315-322, 1988.

11. Momburg, F.. and Koch, S. Selective loss of beta2-microglobulin mRNA inhuman colon carcinoma. J. Exp. Med., 169: 309-314, 1989.

12. Natali, P. G., Nicotra, M. R., Bigotti, A., Venturo, L, Marcenaro, L.,Giacomini, P., and Russo. C. Selective changes in expression of HLA classI polymorphic determinants in human solid tumors. Proc. Nati. Acad. Sci.USA, «6:6719-6723, 1989.

13. Natali, P. G., DeMartino, C.. Quaranta, V., Nicotra, M. R., Frezza, F.,Pellegrino, M. A., and Ferrone, S. Expression of la-like antigens in normalhuman nonlymphoid tissues. Transplantation (Baltimore), 31: 75-79, 1981.

14. Mayer, L., and Shlien, R. Evidence for function of la molecules on gutepithelial cells in man. J. Exp. Med., 766: 1471-1483, 1987.

15. Bernards, R., Dessain, S. K., and Weinberg, R. A. N-myc amplificationcauses down-modulation of MHC class I antigen expression in neuroblastoma. Cell, 47: 667-674, 1986.

16. Versteeg, R., Krusse-Wolters, K. M., Plomp, A. C., Leeuwen, A. V., Stam,N. J., Ploegh, H. L., Ruiter, D. J., and Schrier, P. I. Suppression of class Ihuman histocompatibility leukocyte antigen by c-myc is locus specific. J.Exp. Med., 170: 621-635, 1989.

17. Vogelstein. B.. Fearon, E. R., Hamilton, S. R., Kern. S. E., Preisinger, A.C., Leppert, M., Nakamura, Y., White, R.. Smits, A. M. M, and Bös,J. L.Genetic alterations during colorectal-tumor development. N. Engl. J. Med.,319: 525-532, 1988.

18. Sunday, M. E., Isselbacher, K. J., Gattoni-Celli, S., and Wille«,C. G. Alteredgrowth of a human neuroendocrine carcinoma line after transfection of amajor histocompatibility complex class I gene. Proc. Nati. Acad. Sci. USA,«0:4700-4704, 1989.

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1990;50:8023-8027. Cancer Res   Carl J. McDougall, Sing Shang Ngoi, Ira S. Goldman, et al.   CancerReduced Expression of HLA Class I and II Antigens in Colon

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