Proc. Nat. Acad. Sci. USAVol. 69, No. 4, pp. 1026-1032, April 1972

Relations between Immunity and Malignancy

ROBERT A. GOOD

Departments of Pathology, Pediatrics, and Microbiology, University of Minnesota,Minneapolis, Minn. 55455

ABSTRACT A higher incidence of malignancy as wellas greater susceptibility to infection has been found to beassociated with primary immunodeficiencies. An in-creased incidence of leukemia has been associated withX-linked infantile agammaglobulinemia-an isolateddefectof humoral immunities. An increased frequency of a widevariety of malignancies have been found to accompanyseveral different forms of primary immunodeficiency.Secondary immunodeficiencies produced by immuno-suppressant therapy to facilitate renal transplantationhave also been found to have far too much cancer to beexplained by chance association. Many experimentalassociations between immunity and malignancy havealso been encountered, indicating that these two adaptiveprocesses have an essential relationship that must beelucidated.

An area in rapid development, and hence one of considerablecontroversy is that which was opened by a postulate ex-

pressed by Lewis Thomas in 1958 (1). It was Thomas' conceptthat transplantation immunity as defined in the extraor-dinary analysis of Medawar (2) must play a major role inthe body economy. Thomas could not visualize this new formof immunity as having its high specificity and destructivepotential, either as a mechanism placed in the body to con-

found aspiring transplantation surgeons or as a basis fordiagnosis of persisting bacterial infections, e.g., tuberculosis.Rather, he reasoned that the mechanism must have a raisond'etre directed toward destruction of cells or tissues, whichwhen arising de novo in the body would be recognized as

foreign and would be eliminated by a major line of defense.Thus, Thomas originally stated a hypothesis that has sub-sequently been popularized as the concepts of immuno-surveillance especially in the writings of Burnet (3). This viewhas been vigorously discussed, and right or wrong, thepostulate has served its purpose. It has generated a greatamount of new information concerning the relationshipbetween immunity and malignancy (4).My own relationship to this postulate derived from the

fact that I, a former student and colleague of Thomas, was

heavily engaged at the time in studying the nature of theimmunologic deficit in patients suffering from primary andsecondary forms of immunodeficiency diseases (5). A corollaryof the postulate was that immunodeficient patients, lesscapable than normal of rejecting skin allografts, should notonly reveal their immunodeficiency in increased susceptibilityto infection, but should have too much cancer when comparedto immunologically competent persons. At the time Thomasexpressed this prediction, we were already working intensivelywith several forms of immunodeficiency disease and investi-gating the relations between structure and function in thelymphoid apparatus in the perspective of such patients as

Experiments of Nature.

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Leukemia in Bruton-type agammaglobulinemia

Particularly important to us at the time were studies ofpatients who had selective deficiency of immunoglobulinsynthesis and secretion, failure of antibody production,absence of plasma cells from bone marrow and lymphoidtissues, and deficiency of germinal centers and cell populationsin the far cortical areas of lymph nodes (6-9) (Fig. 1). Recentwork by Cooper and associates (10) and Grey et al. (11) showthat such patients lack B cells as well as plasma cells. We hadfound that these patients often cannot form antibody evenin response to repeated and most intense antigenic stimula-tion.

Their cellular immunologic vigor was quite good andprobably intact (12, 13). Such patients have been found todevelop delayed allergic responses normally, to show anddevelop contact allergy with vigor, and to have lymphocytesthat respond to kidney-bean extract (phytohemagglutinin)in vitro and to allogeneic (of different genetic constitution)lymphocytes in mixed leukocyte culture quite normally (14).We have studied the capacity for allograft rejection inseveral of these patients with Bruton-type agammaglobulin-emia. Usually they will recognize and reject a skin allograftquite normally. They often show a significant delay, however,in the rejection of an initial skin graft, but can show a vigoroussecond set skin-graft rejection (14). Thus, even though suchpatients cannot form circulating antibodies, they do not lackimmunity and one can transfer cellular immunity to non-sensitized normal persons by injecting, intradermally, bloodlymphocytes of patients with Bruton-type agammaglobulin-emia (15). Through the years, some 50 or so patients withBruton-type agammaglobulinemia have been discovered,studied, and reported. Of these five have apparently developedmalignancy, and in each instance the malignancy has beenleukemia (Table 1). None, thus far, have developed carcinomaor solid tissue sarcoma, or even lymphosarcoma. This inci-dence of leukemia-about 10%, stands far in excess of thatobserved in members of the general population of the sameage (16,17).

Immunodeficiency in patients with Hodgkin's disease

At the same time, we were concerned with the immuno-deficiency in patients with Hodgkin's disease. Schier (18)had pointed out that such patients often are anergic. Welooked at this question and confirmed Schier's findings (19).We then showed that anergy often progresses with pro-gression of the disease (20), extends to a frequent deficiencyin vigor of skin allograft rejections (21), and cannot readilybe corrected by giving leukocytes from normal sensitivedonors (5, 15, 19, 21-23). In some of these experiments, what

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Relations between Immunity and Malignancy 1027

we considered massive leukocyte infusions from sensitizeddonors were tried, and they regularly failed to sensitize thenonsensitized patient with Hodgkin's disease. By contrast,patients with Hodgkin's disease produced antibodies well inresponse to many antigenic stimulations. They regularlypossessed in their circulation at least normal amounts of allimmunoglobulins, had plenty of plasma cells in their hemato-poietic tissues, and produced germinal centers in the lymphnodes, usually after antigenic stimulation. As a counterpointexperiment of nature to the patients with Bruton-typeagammaglobulinemia (a B-cell immunodeficiency), patientswith Hodgkin's disease exhibited a deficiency of T-cell butnot of B-cell-dependent immune functions. In these sameterms, it was clear that B-cell immune functions are regularlydeficient in multiple myeloma, while T-cell functions arequite intact (24). In chronic lymphatic leukemia, a diseaseapparently based on monoclonal proliferation of B-cells (25),both T- and B-cell immunities are deficient early in the courseof the disease (26, 27).Even in these early analyses that were surely crude by

present standards, it was clear that in advanced and ad-vancing malignancy, deficiency of cellular immunity is afrequent concomitant. Thus, Southam et al. (28) and Kellyet al. (20) studied in cancer patients, cellular immunity tocancer cells, skin allografts, and antigens against whichcellular immunity is widespread in the general population.They, thus, defined a high frequency of anergy of cellularimmune functions not only in patients with Hodgkin'sdisease but in those with advanced malignancies as well.

Ataxia-telangiectasia

Before we studied the immune responses, immunoglobulinconcentrations and lymphoid tissues of patients with ataxia-telangiectasia, this disease was considered primarily to be aneurological disorder (29-31). This disease, however, isfeatured by an association of progressive cerebellar ataxia,telangiectases of the sclera and skin, especially the skin ofthe eyelids, anticubital, and'popliteal regions. These patientsalso showed an increased frequency of sinopulmonary in-fection (31, 32). The disease has been considered to be anautosomally inherited disorder, but Lambrechts and Snoijink(32) have recently presented arguments that it may be basedon an isoimmunization, and J. Finstad and R. A. Good(unpublished observations) have proposed that if this isindeed an isoimmunization, it might be due to isoimmuniza-tion against the human homologue of the isoantigen 0 in themouse. The isoantigen is distributed in the central nervoussystem and in peripheral lymphoid cells of the T-cell class.The immunological deficiency in patients with ataxia-telangi-ectasia includes frequent (60-70% of patients) deficiency orabsence of IgA, frequent absence of IgE, and regular de-ficiency of cellular immune vigor (31-35). Concordant withthe abnormality of cellular immunity in these patients is aconsistent abnormality of the thymus. The thymus is usually

TABLE 1. Leukemias in infantile, X-linked immunodeficiency

Acute lymphocytic leukemiaMalignant lymphomaChronic monomyelogenous leukemiaThymoma with leukemiaLymphatic leukemia

FIG. 1. Lack of germinal centers in the cortical area of a lymphnode from a patient with X-linked infantile agammaglobuli-nemia.

small, does not show cortical and medullary differentiation,contains very few lymphocytes, and does not contain Hassall'scorpuscles (34). The thymus, indeed, has the appearance ofan embryonic thymus that is just developing a lymphoidstructure. This form of immunodeficiency is important in thecontext of our present analysis because one of the frequentcauses of death in these unfortunate children is malignancy.Malignancies are frequently reticulum-cell sarcoma, lympho-sarcoma, and leukemia, but epithelial malignancies, especiallyof the gastrointestinal tract and malignancies of other sup-porting tissue and mesenchymal tissues have been reportedas well (17, 33). Indeed, the incidence of malignancy inpatients of this group has been about 10% of all collectedcases. This high incidence is all the more striking, because itis occurring at an age in childhood and early life when thefrequency of malignancy is otherwise very low (17).

Malignancy in the Wiskott-Aldrich syndrome

A completely different form of immunodeficiency of man isrepresented by the Wiskott-Aldrich syndrome. In this diseasethe triad of (i) increased tendency to bruise and bleed be-cause of low platelet count and possibly abnormal platelets(ii) increased susceptibility to infection and (iii) an atopic-like eczema are associated (36, 37). The increased sus-ceptibility to infection (38) is associated with a dual systemimmunodeficiency of peculiar nature. Patients with Wiskott-Aldrich syndrome have frequent and progressive deficit ofcell-mediated immunity, deficiency in the concentration ofcirculating IgM, and frequently massively elevated con-

Proc. Nat. Acad. Sci. USA 69 (1972)

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TABLE 2. Malignancies in patientswith primary immunodeficiency

Approximate no. of %Primary disease malignancies collected Cancer

Bruton-type agam- Five cases, all leukemia 5-10maglobulinemia

Ataxia-telangiectasia 42 Cases, many forms of cancer 10-15Wiskott-Aldrich 13 Cases, mostly but not exclu- >10syndrome sively lymphoreticular malig-

nan ciesCommon variable More than 30 cases, many forms 5-10immunodeficiency of cancer

Severe dual system Three cases 1-10immunodeficiency

centrations of IgA and IgE. These patients fail to respond withantibody production or with development of cellular im-munity to polysaccharide antigens, e.g., pneumococcuspolysaccharide, Vi antigen, blood group antigens, and thecellular antigens that give rise to heterolysins (39-41). Bycontrast, they make both IgM and IgG antibodies to proteinantigens very well. Patients with Wiskott-Aldrich syndromeare susceptible to virus, fungus, and bacterial infection, andto both high-grade, encapsulated bacterial pathogens and themore frequent low-grade pathogens (38, 39). In this diseasealso, malignancy occurs far too frequently (17). The mostcommon form of malignancy is a strange reticulum-cellmalignancy that frequently occurs in the brain as well as inthe lymphoid and hematopoietic organs (42). Occassionally,but certainly too frequently to be explained by chance, othermalignancies including epithelial malignancies have beenencountered in these patients (17). The incidence of malig-nancy in children with the Wiskott-Aldrich syndrome isgreater than 10%, and thus again represents a fantasticexcess over that encountered in the general population.

Malignancy in patients with the common

variable immunodeficiency

Among the most frequent of the immunodeficiency syndromeshave been observed in the patients with what has beendescribed in the past as acquired agammaglobulinemia,late-occurring immunodeficiency, sporadic immunodeficiency,abrotropic immunodeficiency, familial immunodeficiency withautoimmune disease, and dysgammaglobulinemia of varioustypes. Whether this is a single disease or multiple entitiesyet to be separated remains to be resolved (43, 44). As agroup, these patients regularly can be shown to have a highfrequency of autoimmune disease, a high frequency of accom-panying hematological abnormality, increased frequency ofbacterial, virus, and even fungus infection. The immuno-logical deficiency, likewise, is variable in severity, but regu-larly can be shown to involve both the T and B cells. Althoughvaliant efforts have been made to classify and subclassifythese patients, the variability from time to time in the same

patient and between members of the same family has arguedagainst fine sublcasses at this juncture (43). Particularly, wehave found the concept of consistent forms of dysgamma-globulinemia (45) spurious at best, and we thus, no longeruse the term. In some instances an autosomal recessivepattern in families of these patients is clear; in other instances

dominant inheritance of a trait that may be expressed in oneindividual as a primary immune deficiency and in otherfamily members as mesenchymal disease has been encountered(46). Still other cases seem to occur sporadically that would,of course, be compatible with recessive inheritance. Recentstudies in our laboratory, as well as in several others, e.g.,that of Cooper et al. (10, 11, 14, 47, and unpublished observa-tions) indicate that these patients possess B cells, but do notdevelop secretory B cells or plasma cells normally. Quantita-tive studies in our laboratory indicate that very regularly suchpatients have fewer than normal responding T cells as well(48). As with the patients with ataxia-telangiectasia andWiskott-Aldrich syndrome, these patients too are developingcancer in an incidence that approaches 10% (17). Themalignancies encountered are often of the lymphoid systemor of the reticular apparatus, but may be epithelial, especiallyinvolving stomach, colon, and intestinal epithelium as well.The incidence of malignancy encountered in the severalimmunodeficiencies is summarized in Table 2.

Chediak-Higashi anomaly

Still another human disease in which increased susceptibilityto infection and malignancy are associated is the so-calledChediak-Higashi anomaly (49). Patients with this disorder,from an early age, are susceptible to recurrent infectionsespecially of the gastrointestinal and respiratory systems.If they do not die of infection, they die of malignancy (50).The malignancy is often diagnosed as lymphosarcoma orHodgkin's disease. Although the immunologic basis of theirsusceptibility to infection is not yet clear, they have a granularabnormality that involves lymphocytes, polymorphonuclears,eosinophils, as well as cells of many organs and tissues. Itseems certain that this abnormality of single membrane-bound particles in some way accounts both for the immuno-deficiency and the increased frequency of malignant disease.

Severe dual-system (cellular and humoral)immunodeficiency and DiGeorge syndrome

Already several cases of malignant disease have turned up inpatients with severe dual-system immunodeficiency (17),even though the children with this disorder generally liveonly a short time. To the knowledge of the writer none havebeen encountered in the few patients with the so-calledDiGeorge syndrome. Further studies of these relationshipsare, however, warranted particularly now that these patientsare being partially and/or completely corrected by thymusand/or marrow transplantation.

Immunologic perturbations during oncogenesiswith chemical carcinogen

As early as 1952, Malmgren et al. (51) noted that severalcarcinogenic chemicals are also immunosuppressive, whereasclosely related compounds are neither immunosuppressive norcarcinogenic. Extensive subsequent studies have since beenperformed that attest to the intimacy of these two influences(52, 53). Surely, the immunosuppressive quality of thechemical carcinogen need not be expressed in vivo in orderto yield a carcinogenic influence, since cells have been trans-formed in vitro to putative malignant state where no influenceon the immune response need be considered (54). Further,the dosage of chemical carcinogen needed to exercise ademonstrable immunosuppressive effect may far exceed theconcentration necessary to exercise a carcinogenic influence

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Relations between Immunity and Malignancy 1029

in vivo (55). Nonetheless, the parallelism of the two cellularinfluences cannot represent a chance association. Prehn (56)particularly has been concerned with these interrelationshipsand has recorded that tumors that are produced by agentslike methylcholanthrene that induce malignancy rapidlyin vivo are likely to be more powerful immunosuppressantsthan agents like plastic that induce malignancy more slowly.Further, malignancies that develop rapidly under powerfulchemical carcinogens are likely to have more readily demon-strable antigenicity in animals syngeneic to those in whichthe tumor developed than are the tumors that develop underweaker carcinogenic influence, where longer incubationperiod is required.

Influence of experimental iinmunosuppressionon development of malignancyOn the other side of the coin, we find evidence that immuno-suppressive regimens in experimental animals foster thedevelopment of malignancies de novo and also may foster theoccurrence and establishment of metastases (17, 57). Someevidence has been presented that immunosuppressive regi-mens including thymectomy (58), and even antilymphocyteserum foster the development of malignancies induced bychemical carcinogens. In this regard, it is important toconsider Allison's (59, 60) more recent analysis that indicatesthat with certain immunosuppressive regimens, only themalignancy induced by oncogenic virus(es) is influenced byimmunosuppressive agents that are not themselves chemicalcarcinogens.Immunosuppression and Transplantation of Cancer in Man.

Soon after clinical trials of kidney allotransplantation wereintroduced some 10 years ago, it became apparent that inman, as in experimental animals, allotransplants of malignantcells could be achieved in immunosuppressed persons. Atleast nine such transplants of malignancy occurred in-advertently (17, 52, 61). In each instance, the transplantedmalignancy was epithelial in nature, and in four instancesthe malignancies became widely disseminated throughout thebody. To achieve complete regression of these widely dis-seminated malignancies, the only treatment required inseveral instances was cessation of the immunosuppressiveregimen (52, 61). Once this had been done, the widely dis-seminated malignancy just like the allogeneic organ transplant,was rejected. Thus, under these artificial circumstances, thepotential power of the allograft mechanism for eliminatingeven widely disseminated malignancy was demonstrated.Immunosuppression and the Development of Malignancy

De Novo in Man. The extension of clinical transplantationhas witnessed progressive improvement of skill at immuno-suppression. This development has been signalled by increasingsuccess in organ transplantation. At the present writingrenal transplantation is, indeed, a therapeutic fiat accompliand renal transplants from well matched sibling donorsshould not be rejected and can serve as long term therapyfor patients with end-stage renal disease. Relatives obviouslynot matched at the HL-A histocompatibility determinantsalso can donate kidneys with the expectancy that the graftsin a high percentage of instances (greater than 80% in someseries) will provide long term life-saving renal function.Even cadaver donors in 60% of instances provide long termcorrection of renal failure for many recipients. Such immuno-

regularly to permit cardiac, liver, pancreas, or even marrow

transplants, and they often cannot control graft-versus-hostreactions. It is to be expected that this approach will beimproved and even more powerful immunosuppressivetherapy will be developed that will extend the transplantationera. One complication of these immunosuppressive regimensmight be anticipated from the Thomas' postulate (1). Im-munosuppression, powerful enough to depress organ and cellrejection from allogeneic donors, might foster developmentof malignancy. This prediction has apparently been borne outbecause about a 10-fold increase in incidence of malignancyhas been observed in patients given an organ transplantunder immunosuppressive therapy (17, 62, 63). The malig-nancies and tumors that have developed have been approxi-mately equally divided among tumors of epithelial andlymphoreticular origins (63-65). The four tumors of whichwe have seen in the Minnesota series have all been epithelialin nature. One was an anaplastic carcinoma, one was an

ovarian carcinoma, and two were carcinomas of the cervixuteri. The frequently indicated association between lympho-reticular malignancy and antilymphocyte serum (66) is notsufficiently inclusive. Malignancies occur with greater fre-quency than normal when immunosuppression is accomplishedwithout antilymphocyte serum (64). Further, epithelial as

well as lymphoreticular malignancies are observed in patientswhose immunosuppressive regimen includes antilymphocyteserum (17, 64). All these relationships are to be predicted fromthe surveillance hypothesis.

Direct evidence for the relation betweenimmunity and malignancy

For a number of years, evidence has been accumulating thatreflects in still another perspective the essentiality of an

immunity-malignancy interface. Wherever they can beeffectively studied in experimental animals, malignant tumorsand malignant cells can be shown to have at their surfaceantigens that are foreign to the host (66-68). These antigensare called tumor-specific transplantation antigens (TSTA)as a reflection of the methods used for their demonstration.They differ in chemical-carcinogen and virus-induced malig-nancies in that the tumor-specific transplantation antigensfor virus-induced malignancies tend to reflect the virus induc-tion and are similar for all the tumors induced by the virus inquestion. Thus, in experimental animals, whether a polyomavirus-induced malignancy is a mesenchymal or an epithelialmalignancy, sharing of this antigen is to be found. By con-

trast, chemical carcinogen-induced malignancies tend tohave tumor antigens that reflect the particular induction tomalignancy. Thus, two different malignancies arising withinthe same animal by virtue of the influence of methylcholan-threne will possess tumor-specific transplantation antigensthat are different. The same will be true if dibenzanthracenehas been used as the chemical carcinogen. Similarly, humanmalignant tumors are being found in which tumor-specificantigens are present at the surface. In its ultimate con-

sideration, this consistent relationship between immunityand malignancy means that cells that should be looked on bythe host as being foreign are not being eliminated from thebody by immunologic means. In experimental systems, as

for example in mice infected with Maloney sarcoma virus(69) and in rabbits infected with Shope papilloma virus (70),

suppressive regimens, however, are not powerful enough

Proc. Nat. Acad. Sci. USA 69 (1972)

one sees progressor and regressor states of the potential

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malignancy. The analysis of the progressor and regressoradaptations in immunological terms by the Hellstroms (71)and their associates have revealed that in the regressors,cell-mediated immunity in the form of a killer function oflymphocytes is directed toward the tumor cells. Serum of theanimals does not interfere or oppose this action. By contrast,in the progressor status, cellular immunity directed againstthe tumor cells can be demonstrated, but the tumor seems tobe protected from destruction by blocking antibodies incirculation that inhibit this action. Similarly, in rabbitsinfected with Shope-papilloma virus, a regressor state isassociated with cellular immunity, while in the progressorstate a humoral immunity seems to exist that can interferewith the destructive action of the cellular immunity on thetumor cells.Much evidence has now accumulated to indicate that in

numerous experimental systems and in many different humanmalignancies, cellular immune reactions directed againstmalignancy exists concomitantly with blocking antibodiesthat are able to interfere with the killer action of the lympho-cytes against the tumor cells (72). These exciting phenomenamay well be extensions of the enhancement phenomenondiscovered for certain experimental situations long ago (73).I have used the term immunodeviation to describe thisclass of reactions.A possible alternate means of circumventing cellular and

humoral tumor immunity that might destroy malignant cellsincludes immunological tolerance, but this has not yet beenclearly defined for tumor-host relationships any more than ithas for other forms of cellular immunity directed againstforeign cells. Other possible mechanisms by which tumorcells can avoid effective immune reactions include antigenicmodulation (74), already known for both human and animaltumor cells (70) and inhibition of "the cellular display" ofAlexander and others in development of immunity (75).

Oncogenic viruses as immunosuppressantsWorking with the Gross passage A virus, Peterson, Dent, andI (76, 77) discovered that oncogenic viruses can suppresscellular as well as certain humoral immune adaptations. Inmore lateral studies, similar profound influences of variousoncogenic viruses on different immune responses have beendiscovered (78). Indeed, it seems a characteristic of manyoncogenic and nononcogenic viruses that they have capacityto inhibit development and expression of immune reactions,especially cellular immune reactions (79). The temporary andlong-term influences of oncogenic viruses on cellular immunefunctions needs much more study, especially at a molecularlevel. Certainly, the capacity of the cells involved in cellularimmunity to synthesize protein, DNA, and RNA in responseto mitogenic stimuli as with phytohemagglutinin (80-82),allogeneic cells, or antigen can be profoundly influenced byexposure to viruses like rubella virus, rubeola virus, or New-castles disease virus.

Relation between nutrition, immunity, and malignancyBeginning with studies by Moreschi in 1909 (83) and Rousin 1914 (84) an abundant literature has accumulated indi-cating that experimental animals that are nutritionallydeprived are less prone to develop various malignancies thanare well-nourished animals. Protein nutritional deprivationand deprivation of essential amino acids particularly inhibit

coveries by Jose, Cooper, and me (reviewed) (85) have re-

vealed that chronic protein or amino-acid deprivation can

have as one consequence profound depression of capacity toproduce humoral immunity and blocking antibody against tu-mor cells in xenogeneic, allogeneic, and syngeneic animals,while leaving cellular immunity intact or even enhancing it.More profound nutritional deprivation can yield deficienciesof both cellular and humoral immunity. It seems possible fromcursory study of the literature as well as from our own

experimental results that difficulty in developing malignancyin the presence of nutritional deprivation may relate to thedifferential influence of certain forms of nutritional depriva-tion on the T- and B-cell immunities.

Relation between aging, immunity, and malignancy

Another interesting relation exists between immunity andmalignancy that is revealed in aging (86). With aging,immunologic vigor, especially the vigor of cellular immunityshows remarkable decline in many strains of mice. By con-

trast, capacity to form immunoglobulins and autoantibodiesseems to be retained longer (87). Thus, a lack of immuno-logical balance occurs frequently in aged mice that couldfavor immunodeviation of the sort that in experimentalanimals fosters success of the malignant adaptation (88).Similar cellular immunodeficiency can also occur with agingin man. Much study to extend, quantitate, and evaluate theserelationships seems warranted in light of the frequent oc-currence of certain forms of malignancy with age in mice andmen, and the greater propensity of aged animals to accepttransplants of malignant cells (3).

The meaning of the interfaces

These many interfaces between the malignant adaptation on

the one hand and immunologic adaptation on the other,suggest that these two adaptive processes have been inter-acting in some important and possibly essential way for avery long period. There can be no question that Thomas'postulate has been useful. VWhether it is correct is anothermatter. Prehn has beautifully summarized evidence, whichhe believes argues against the concept of immunosurveillance(54). By contrast, he visualizes the essential relation betweenimmunity and tumor antigenicity in another way, namely,that the tumor-specific antigens and the nonself nature of themalignant cells may in some way be essential to their ex-pression of a malignant nature. Whichever view is correct, itseems that the foreignness of malignant cells will be used todetect the occurrence of malignancy and perhaps even toprevent and treat the malignant process. In the latter direc-tion, the carcinoembryonic antigens first looked at by Goldand Freedman (89), Uriel (90) and others, as well as thetumor-specific transplantation antigens, hold promise. Crudeefforts at immunotherapy already are being attempted (91).Bone marrow transplantation (92), thymic transplantation

(93, 94), and the use of transfer factor (95) represent thefirst steps in correction of the immunodeficiencies that asmodel systems have taught us so much about the developmentand organization of the lymphoid system. Ultimately,somatic cellular genetic analysis, genetic engineering, andcellular engineering applied to these diseases can give uspowerful new approaches for correction of these and otherimmunologic deficits that underly development of malig-

development of malignancy in many systems. Recent dis-

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Relations between Immunity and Malignancy 1031

The author is an American Legion Memorial Research Profes-sor Regents' Professor of Pediatrics, Pathology, and Microbi-ology. Aided by grants from the American Cancer Society, TheNational Foundation-March of Dimes, and U.S. Public HealthService (AI-08677), and contract from the Special Cancer VirusProgram (NIH 71-2261).

1. Thomas, L. (1961) in Cellular and Humoral Aspects of theHypersensitive States, ed. Lawrence, H. W. (Hoeber-Harper,New York), pp. 529-532.

2. Medewar, P. B. (1961) in Cellular and Humoral Aspects ofthe Hypersensitive States, ed. Lawrence, H. S. (Hoeber-Harper, New York), pp. 504-529.

3. Burnet, F. M. (1970) in Progress in Experimental TumorResearch (Karger, Basel), pp. 1-27.

4. Smith, R. T. & Landy, M. (eds.) (1970) Immunological Sur-veillance (Academic Press, New York).

5. Good, R. A., Kelly, W. D., Rotstein, J. & Varco, R. L.(1962) in: Progress in Allergy (Karger, Basel and NewYork), pp. 187-319.

6. Good, R. A. (1955) J. Lancet 75, 245-271.7. Good, R. A. (1954) Revue Hematol. 9, 502-503.8. Good, R. A. (1955) J. Lab. Clin. Med. 46, 167-181.9. Peterson, R. D. A., Cooper, M. D. & Good, R. A. (1965)

Amer. J. Med. 38, 579-604.10. Cooper, M. D., Lawton, A. R. & Bockman, D. E. (1971)

Lancet ii, 791-794.11. Grey, H. M., Rabellino, E. & Pirofsky, B. (1971) J. Clin.

Invest. 50, 2368-2375.12. Good, R. A., Zak, S. J., Jensen, D. R. & Papenheimer, A. M.,

Jr. (1957) J. Clin. Invest. 39, 894.13. Good, R. A. & Zak, S. J. (1956) Pediatrics 18, 109-149.14. Good, R. A. (1971) in Progress in Immunology, ed. Amos, B.

(Academic Press, New York), pp. 699-722.15. Good, R. A., Varco, R. L., Aust, J. B. & Zak, S. J. (1957)

Ann. N.Y. Acad. Sd. 64, 882-924.16. Page, A. R., Hansen, A. E. & Good, R. A. (1963) Blood 21,

197-206.17. Gatti, R. A. & Good, R. A. (1971) Cancer 28, 89-98.18. Schier, W. W., Roth, A., Ostroff, G. & Schrift, M. H. (1956)

Amer. J. Med. 20, 94-99.19. Kelly, W. D., Good, R. A. & Varco, R. L. (1958) Surg.

Gynec. Obstet. 107, 565-570.20. Lamb, D., Pilney, F., Kelly, W. D. & Good, R. A. (1962) J.

Immunol. 89, 555-558.21. Kelly, W. D., Lamb, D. I., Varco, R. L. & Good, R. A.

(1960) Ann. N.Y. Acad. Sd. 87, 187-202.22. Good, R. A., Kelly, W. D. & Gabrielsen, A. E. (1962) in

Second International Symposium on Immunopathology, BennoSchwabe & Co. (Basel, Switzerland), pp. 353-384.

23. Warwick, W. J., Archer, 0. K., Kelly, W. D. & Page, A. R.(1961) Fed. Proc. 20, 18-00.

24. Zinneman, H. H. & Hall, W. H. (1954) Ann. Inter. Med. 41,1152-1163.

25. Seligmann, M. (1971) Presented on section of Immune Dis-orders of Man panel at First Internatiqnal Congress of Im-munology. In Progress in Immunology (Academic Press,New York).

26. Cone, L. & Uhr, J. W. (1964) J. Clin. Invest. 43, 2241-2248.27. Dent, P. B., Peterson, R. D. A. & Good, R. A. (1968) in

Immunologic Deficiency Diseases in Man, Birth DefectsOriginal Articles Series, eds. Good, R. A. & Bergsma, D.(National Foundation Press, New York), pp. 443-458.

28. Southam, C. M. (1961) Cancer Res. 21, 1302-1316.29. Louis-Bar (1941) Confin. Neurol. 4, 32-42.30. Boder, E. & Sedgwick, R. P. (1963) Little Club Clin. Develop.

Med. 8, 110-118.31. Boder, E. & Sedgwick, R. P. (1963) in Cerebellum, Posture

and Cerebral Palsy, ed Walsh, G. (London), pp. 110-118.32. Lambrechts, A. F. & Snoijink, J. J. (1971) Ataxia telangi-

ectasia. Morbus Lympholyticus Congenitalis (J. E. Bush-mann, Antwerpen, Belgium).

33. Peterson, R. D. A., Kelly, W. D. & Good, R. A. (1964)Lancet i, 1189-1193.

34. Peterson, R. D. A. & Good, R. A. (1968) in ImmunologicDeficiency Diseases in Man, Birth Defects Original Article

Series, eds. Good, R. A. & Bergsma, D. (National Founda-tion Press, New York), pp. 370-377.

35. Biggar, W. D., Lapointe, N., Ishizaka, K., Meuwissen, H.,Good, R. A. & Frommel, D. (1970) Lancet ii, 1089.

36. Wiskott, A. (1937) Monatsschr. Kinderheilk 68, 212-214.37. Aldrich, R. A., Steinberg, A. G. & Campbell, D. C. (1954)

Pediatrics 13, 133-139.38. St. Geme, J. W., Jr., Prince, J. T., Burke, B. A., Good, R. A.

& Krivit, W. (1965) N. Engl. J. Med. 273, 229-234.39. Cooper, M. D., Chase, B. P., Lowman, J. T., Krivit, W. &

Good, R. A. (1968) in Immunologic Deficiency Diseases inMan. Birth Defects Original Article Series, eds. Good, R. A.& Bergsma, D. (National Foundation Press, New York), pp.378-387.

40. Cooper, M. D., Chase, H. P., Lowman, J. T., Krivit, W. &Good, R. A. (1968) Amer. J. Med. 44, 499-513.

41. Blaese, R. M., Strober, W., Brown, R. S. & Waldmann,T. A. (1968) Lancet i, 1056-1061.

42. Ten Bensel, R. W., Stadlan, E. M. & Krivit, W. (1966) J.Pediat. 68, 761-767.

43. Seligmann, M., Fudenberg, H. & Good, R. A. (1968) Amer.J. Med. 45, 817-825.

44. Fudenberg, H. H., Good, R. A., Goodman, H. C., Hitzig,W., Kunkel, H. G., Roitt, I. M., Rosen, F. S., Rowe, D. S.,Seligmann, M. & Soothill, J. R. (1971) Pediatrics 47, 927-946.

45. Rosen, F. S., Craig, J. M., Vawter, G. & Janeway, C. A.(1968) in Immunologic Deficiency Diseases in Man, BirthDefects Original Article Series, eds. Good, R. A. & Bergsma,D. (National Foundation Press, New York), pp. 67-70.

46. Wolf, J. K., Gokcen, M. & Good, R. A. (1963) J. Lab. Clin.Med. 61, 230-248.

47. Pernis, B. & Kunkel, H. (1971) Discussion of Good, Biggar,and Park in Progress in Immunology, ed. Amos, B. (AcademicPress, New York) p. 723.

48. Park, B. H. & Good, R. A. (1972) Proc. Nat. Acad. Sci USA69, 371-373.

49. Windhorst, D. B., Zelickson, A. S. & Good, R. A. (1966)Science 151, 81-83.

50. Page, A. R., Berendes, H., Warner, J. & Good, R. A. (1962)Blood 20, 330-343.

51. Malmgren, R. A., Bennison, B. E. & McKinley, T. W., Jr.(1952) Proc. Soc. Exp. Biol. Med. 79, 484-488.

52. Good, R. A. & Finstad, J. (1969) Nat. Cancer Inst. Monogr.31, 41-58.

53. Stzernsward, J. (1966) J. Nat. Cancer Inst. 37, 505-512.54. Prehn, R. T. (1970) in Immune Surveillance, eds. Smith,

R. T. & Landy, M. (Academic Press, New York), pp. 451-462.

55. Prehn, R. T. (1963) J. Nat. Cancer Inst. 31, 791-805.56. Prehn, R. T. (1964) J. Nat. Cancer Inst. 32, 1-17.57. Klein, G. (1969) Fed. Proc. 28, 1739-1753.58. Defendi, V., Roosa, R. A. & Koprowski, H. (1964) in The

Thymus in Immunobiology. eds. Gabrielsen, A. E. & Good,R. A. (Hoeber-Harper, New York), pp. 504-520.

59. Allison, A. C. & Law, L. W. (1968) Proc. Soc. Rap. Biol.Med. 127, 207-212.

60. Allison, A. C., Berman, L. H. & Levey, R. N. (1967) Nature215, 185-187.

61. Wilson, R. E., Hager, E. B., Hampers, C. L., Corson, J. M.,Merrill, J. P. & Murray, J. E. (1968) N. Engl. J. Med. 278,479-483.

62. McKhann, C. F. (1969) Transplantation 8, 209-212.63. Penn, I., Halgrimson, C. G. & Starzl, T. E. (1972) Trans-

plant. Proc., in press.64. Starzl, T. E., Penn, I. & Halgrimson, C. G. (1970) N. Engi.

J. Med. 283, 934.65. McPhaul, J. J., Jr. & McIntosh, D. A. (1968) N. Engl. J.

Med. 272, 105.66. Klein, G. (1966) Is. J. Med. Sci. 2, 135-142.67. Prehn, R. T. & Main, J. M. (1957) J. Nat. Cancer Inst. 18,

769-778.68. Smith, R. T. (1968) N. Eng. J. Med. 278, 1207-1214, 1268-

1275, and 1326-1331.69. Hellstrom, I. & Hellstro1n, K. E. (1969) Int.J. Cancer 4,

587-600.

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70. Hellstrom, I., Evans, C. A. & Hellstrom, K. E. (1969) Int.J. Cancer 4, 601-607.

71. Hellstrom, K. E. & Hellstrom, I. (1970) Hosp. Pract. 5, 45-61.

72. Hellstrom, I., Hellstrom, K. E., Sjogren, H. 0. & Warner,G. A. (1971) Int. J. Cancer 7, 1-16.

73. Kaliss, N. & Fitch, F. W. (1971) in Progress in Immunology,ed. Amos, B. (Academic Press, New York), pp. 1545-1547.

74. Old, L. J., Stockert, E., Boyse, E. A. & Kim, J. H. (1968)J. Exp. Med. 127, 523-539.

75. Alexander, P. (1968) Progr. Exp. Tumor Res. 10, 22-71.76. Peterson, R. D. A., Hendrickson, R. & Good, R. A. (1963)

Proc. Soc. Exp. Biol. Med. 114, 517-520.77. Dent, P. B., Peterson, R. D. A. & Good, R. A. (1965) Proc.

Soc. Exp. Biol. Med. 119, 869-871.78. Friedman, H. & Ceglowski, W. S. (1971) in Progress in Im-

munology, ed. Amos, B. (Academic Press, New York), pp.815-829.

79. Olson, G. B., Dent, P. B., Rawls, W. E., South, M. A.,Montgomery, J. R., Melnick, J. L. & Good, R. A. (1968)J. Exp. Med. 128, 47-68.

80. Rawls, W. E., Melnick, J. L., Olson, G. B., Dent, P. B. &Good, R. A. (1968) Science 158, 506-507.

81. Montgomery, J. R., South, M. A., Rawls, W. E., Melnick,J. L., Olson, G. B., Dent, P. B. & Good, R. A. (1967) Science157, 1068-1070.

82. Olson, G. B., South, M. A. & Good, R. A. (1967) Nature 214,695-696.

83. Moreschi, C. (1909) Z. Immunitaetsforsch. 2, 651-685.84. Rous, P. (1914) J. Exp. Med. 20, 433-451.85. Jose, D. G., Cooper, W. C. & Good, R. A. (1971) J. Amer.

Med. Ass. 218, 1428-1429.86. Sigel, M. & Good, R. A. (eds.), in Tolerance, Autoimmunity

and Aging (Charles C Thomas, Springfield), in press.87. Yunis, E. J., Stutman, O., Fernandes, G., Teague, P. 0. &

Good, R. A. (1972) in Tolerance, Autoimmunity and Aging,eds. Sigel, M. & Good, R. A. (Charles C Thomas, Spring-field).

88. Yunis, E. J., Stutman, 0. & Good, R. A. (1971) Ann. N.Y.Acad. Sci. 183, 205-220.

89. Gold, P. & Freedman, S. 0. (1965) J. Exp. Med. 122, 467-481.

90. Uriel, J., Nechaud, B. de, Birencwajg, M. S., Masseyeff, R.,Leblanc, L., Quenum, C., Loisillier, F. & Grabar, P. (1967)C.R. Acad. Sci. 265, 75-78.

91. Mathe, G. (1971) Hosp. Pract. 6, 43-51.92. Good, R. A. (1971) J. Amer. Med. Ass. 214, 1289-1300.93. Cleveland, W. W., Fogel, B. J., Brown, W. T. & Kay, H. E.

M. (1968) Lancet ii, 1211-1214.94. August, C. S., Rosen, F. S., Filler, F. M., Janeway, C. A.,

Markowski, B. & Kay, H. E. M. (1968) Lancet ii, 1210-1211.95. Levin, A. S., Spitler, L. E., Stites, D. P. & Fudenberg, H. H.

(1970) Proc. Nat. Acad. Sci. USA 67, 821-828.

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