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96 26 Gronowicz,E. and Coutinho, A. (1974) Eur. J. lmmunol. 4, 771 27 Gronowicz, E. and Coutinho, A. (1975) Scand..7" lmmunol. 4, 429 28 Goodman, M.G., Fidler, J.M. and Weigle, W.O. (1978) .7. Immunol. 121, 1905 29 Bona, C., Yano, A., Dimitriu, A. and Miller, R.G. (1978) J. Exp. Med. 148, 136 30 Claman, H.N., Chaperon, E.A. and Triplet, R.F. (i966) Proc. Soc. Exp. Biol. (NI') 122, 1167 31 Miller, J.F.A.P. and Mitchell, G.F. (1967) Nature (London) 216, 659 32 Gershon. R.K. and Kondo, K. (197l) Immunology21,903 33 Gershon, R.K. (1974) (.Snlemp. Top. Immunobiol. 3, 1 34 Tada, T., Takemori, T., Okumura, K., Nonaka, M. and Tokuhisa, T. (1978)J. Exp. Med. 147, 446 35 Muirhead, D.Y. and Cudkowicz, G. (1978) J. Immunol. 121, 130 36 Shinohara, N. and Kern, M. (1976)J. Immunol. 116, 1607

37 Ballieux, R.E., Heijnen, C.J., Uytdehaag, F. and Zegers, B.J.M. (1979) lmmunol. Rev. 45, 3 38 Goodman, M.G. and Weigle, W.O. (1979) J. lmm~mol. 122, .2548 39 Theofilopoulos, A.N., Shawler, D.L., Eisenberg, R.A. and Dixon, FJ. (1980)j . Exp. Med. 151,446 40 Goodman, M.G. and Weigle, W.O. (1980) Fed. Proe.39, 459 41 Rocklin, R.E., Greineder, D.K. and Melmon, K.L. (1979) Cell. Immunol. 44, 404 42 Primi, D., Hammarstrom, L. and Smith, C.I.E. (1979) (,'ell. Irnmunol. 42, 90 43 Berman, M.A., Speigleberg, H.L. and Weigle, W.O. (1979)J. Immunol. 122, 89 44 Berman, M.A. and Weigle, W.O. (1977)J. Exp. Med. 146, 241 45 Morgan, E.L. and Weigle, W.O. (1980)J. Immunol. 124, 1330 46 Morgan, E.L. and Weigle, W.O. (1980)J. Exp. Med. 151, 1 47 Thoman, M.L., Morgan, E.L. and Weigle, W.O. (1980) Fed. Proc. 39, 665

D o N K cells play a role in antitumor surveillance ? John C. Roder and Tina Haliotis Department of Microbiology and Immunology, Queen's University, Kingston, Ontario, Canada KTL 3N6

A class of lyrnphocytes found in several mammalian species including man will kill cells of many lumor lines in vitro 1-4. There is growing evidence, derived mainly from the work of Kiessling and co-workers, that these natural killer (NK) cells play a role in surveillance against tumor development in vivo. In this article John Roder and Tina Haliotis discuss a hypothesis for anti-tumor surveillance which integrates all of the potentially important immunological systems in the host and gives to N K cells the role of foremost barrier against developing tumors.

The NK hypothesis of tumor s u r v e i l l a n c e N K cells exist in the unstimulated host at high frequency (0.6-2.497o of all lymphocytes s) and do not require a lengthy period of preactivation. O n the basis of these characteristics, one can hypothesize that N K cells provide a first line of defence against a newly arising malignancy or its metastases (Table I). Other potential effector cells such as T cells, activated macrophages or K cells participating in antibodydependent cell-mediated cytotoxicity (ADCC) 6, if they are important at all, would only be effective after a specific priming or activation period requiring days or weeks. It is not unreasonable to assume that under the selective pressure of such a lethal condition as malignancy, several independent defence mechanisms may have evolved. In principle, the hypothesis is an adaptation of the one originally proposed by Thomas v and modified by Burnett 8. However, the role of the T cell in i m m u n e surveillance has not withstood critical test (for reviews see Refs 3 and 9-11). In the scheme shown in Table I and Fig. 1, we have placed the NK cell as the foremost, but not necessarily the only, barrier to tumor development. The mechanism by which the NK cell recog© Elsevier/North-Holland Biomedical PJess 1980

nizes and destroys the developing tumor has been discussed elsewhere12,13. It is, however, instructive to consider some recent work by Collins, Patek, and Cohn 14 which shows a correlation between the tumorigenic potential of cloned, chemically transformed cell lines and their susceptibility to NK-mediated lysis in vitro. N cells, from a cloned fetal fibroblast line which does not grow in agarose, were not tumorigenic in vivo [in normal mice or lethally irradiated mice thymectomized as adults and reconstituted with fetal liver (ATxFL mice)] and were not lysed by NK cells in vitro. W h e n these cells were t r a n s f o r m e d by methylcholanthrene (MCA) they grew in agarose and after cloning could grow as tumors in A T x F L mice ~ which were N K deficient 14 but not in normal mice. This same mutation, N t>I, also made the cells susceptible to NK-mediated cytolysis in vitro. Cell lines derived from these I tumors were capable of growth in normal mice. This I DC mutation, or selection, was accompanied by a loss of N K sensitivity, so that the tumor could escape N K surveillance and grow in normal mice. Although this is a useful model it would be misleading to suggest that NK cells only lyse tumor cells since

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97

® Fig. 1. Anti-tumor surveillance by NK Cells. Shaded cells are dead. Steps I to 6 are explained in Table 1. virus-infected cells, h e m o p o e t i c grafts and even some n o r m a l tissues are NK-sensitive (discussed in o t h e r reviews).

Indirect e v i d e n c e for the h y p o t h e s i s E a r l y evidence that N K cells were involved in rejection of t r a n s p l a n t a b l e t u m o r s in vivo has been reviewed at length elsewhere 3 a n d can be s u m m a r i z e d as follows. (1) In genetic e x p e r i m e n t s there was a strong positive correlation b e t w e e n N K activity in vitro and resistance in vivo to g r o w t h of a n u m b e r of different t u m o r transplants in various strains a n d F 1 crosses or baekcrosses b e t w e e n high- and l o w - N K - r e s p o n d e r genotypes 1~-2°. N K activity in vivo and in vitro was controlled by autosomal, d o m i n a n t , H-2 linked genes. S i m i l a r correlations b e t w e e n N K activity in vitro and in vivo were found in s h o r t - t e r m (4 h) clearance assays in mice injected with t u m o r cells pre-labelted with lzsIUdR2,2~. (2) M u r i n e l y m p h o c y t e s e n r i c h e d for N K cells by depletion of T cells, B cells and m a c r o p h a g e s 22 or by positive selection for i m m u n o g l o b u l i n - n e g a t i v e cells c a r r y i n g Lyt-5 antigen 23 were most effective in inhibiting t u m o r growth w h e n they were transferred to recipients at the t i m e of challenge with tumor. (3) T-cell deficient F 1 hybrid mice = and n u d e mice 22,24 have raised N K activity in vitro and are better able to resist. NK-sensitive syngeneic t u m o r s or their metastases 25 in vivo but less able to reject allogeneic t u m o r s across the H-2 barrier (as expected of T-celldeficient animals). (4) T h y m e c t o m i z e d and irradiated F~ h y b r i d mice r e p o p u l a t e d with T - c e l l - d e p l e t e d b o n e - m a r r o w cells from high- or l o w - N K - r e a c t i v e donors displayed the same in-vivo resistance to a semi-syngeneic t u m o r t r a n s p l a n t Y A C 26 or s p o n t a n e o u s A K R l y m p h o m a s 27 as did the b o n e - m a r r o w donor. (5) A g i n g mice, in general, exhibit an i n c r e a s i n g incidence of spontaneous t u m o r s and are less able to reject NK-sensitive t r a n s p l a n t a b l e tumors 26. It is noteworthy, therefore, that y o u n g mice r e p o p u l a t e d with bone m a r r o w from old mice, and intact old mice had d i m i n i s h e d N K function in vitro 28, T h i s suggests,

but by no m e a n s proves, that the early decline in N K cell activity m i g h t predispose the a n i m a l to later t u m o r development. (A m o r e direct e x p e r i m e n t w o u l d be to a t t e m p t to reduce s p o n t a n e o u s t u m o r incidence in old mice by N K r e p l a c e m e n t therapy.) (6) R a i s e d in-vitro N K activity against Y A C or syngeneic, M C A - i n d u c e d fibrosarcomas in mice deprived of B cells by chronic anti-g t r e a t m e n t , correlated well with an increased resistance to (i) i n d u c t i o n of p r i m a r y t u m o r s by MCA29; (ii) t r a n s p l a n t a t i o n of syngeneic MCA-induced fibrosarcomas29; (iii) spontaneous metastasis from the p r i m a r y t u m o r site 3°. A n i m p o r t a n t control in these studies was the observation that the incidence and g r o w t h - r a t e of progressing tumors induced by M o l o n e y s a r c o m a virus did not differ in anti-g-suppressed or n o r m a l control mice that w e r e u n t r e a t e d or t r e a t e d w i t h n o r m a l g a m m a g l o b u l i n (Gordon, u n p u b l i s h e d observations). Since host defence in the M S V system is clearly T-celld e p e n d e n t 31 this indicates that B-cell-deprived mice have n o r m a l T function and a u g m e n t e d N K activity does not influence a T - c e l l - d e p e n d e n t rejection system. T h e s e six lines of evidence, a l t h o u g h highly suggestive of a role for N K cells in vivo, are not conclusive. T h e evidence rests m a i n l y on an analysis of covariance and the adoptive transfer of partly e n r i c h e d N K populations or their precursors. In m a n y of these experiments it could not be ruled out conclusively that T cells, m a c r o p h a g e s or even n a t u r a l antibodies 9 were TABLE I. The placement of NK cells in a hypothetical sequence of anti-tumor surveillance 1. A neoplastic transformation occurs via somatic mutation, viral or chemical induction s°. 2. Proliferating tumor cells are held in check by NK cells, which pre-exist at high numbers (1-2% of total lymphocyte pool). 3. After a sensitizing period of several days, some of the remaining tumor cells are lysed by immune T cells assuming that the tumor is antigenic (most spontaneous tumors are not). 4. Immune T cells are triggered by tumor antigens to release macrophage-activating factors which induce macrophages to lyse remaining tumor cells. 5. Finally, small amounts of anti-tumor antibody may appear in the circulation and bind to any remaining tumor cells thus rendering them susceptible to ADCC by K cells or NK cells (which may be identical), promonocytes, macrophages and polymorphonuclear leukocytes. 6. Tumor cells escaping from the primary tumor during metastasis are held in check by NK cells during transport to, or at, the metastatic toci (assuming NK-resistant variants have not arisen from the selection process in step 1). All of these mechanisms (see Fig. 1) have been shown to be important in the rejection of some experimental tumors. However, it remains to be determined whether any of them play a role in the prevention of spontaneous tumors and some effectors (T cells, B cells, antibody) have been shown not to be important in this regard. The important point is that NK cells could potentially provide the first level of defence. There is also some evidence to suggest that such a model would be appropriate in surveillance of virally infected cells.

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in some way involved in tumor rejection. Since these parameters were seldom measured the experimental tool most clearly required was a more precise and selective method for abrogating N K function. T h e 'beige' mutant as a model for NK surveillance A m u t a n t gene in the mouse called beige, in the homozygous condition, confers a selective impairment of in-vitro N K function32. In beige mice cytolysis of tumor cells by T cells, activated macrophages, and promonocytes and ADCC against non-tumor targets were normal, as were a variety of other immunological functions (Table II). These mice provide a critical test of the hypothesis that N K cells are a first line of defence against neoplasia.

Tumor growth and dissemination in beige mice As predicted 32, selectively NK-deficient homozygous beige m u t a n t mice (bg/bg) which were deficient in N K activity but otherwise immunologically normal, were more susceptible to the growth and dissemination of t r a n s p l a n t a b l e tumors t h a n were their phenotypically normal, heterozygous littermate controls (+/bg)33,34. As summarized in Table III, bg/bg TABLE Ih Immune functionin beige mice and Chediak-Higashi (CH) patientsa Function

NK cytolysis Frequencyof NK-target-bindingcells ADCC v. tumor cells ADCC v. erythrocytes CTL--MLC In-vivoalloimmune Lectin-induced Skin-graft rejection Delayed-type hypersensitivity T-cell mitogenresponse B-cell mitogensresponse B-cell Igproduction Activated macrophage cytolysis Promonocytecytolysis Spontaneous ADCC NK interferonboost Cyclic GMP restoration in NK function Lysosomalenzymefunction

bg/bg

CH mice patients

Low Normal Low Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal

Low Normal Low Normal Normal ND NormMc Normal Normal Normal Normal Normal Normal

Normal Normal Normal ND Yes b

Yes b

No Low

Yesc Low

aHomozygous bg/bg mice were compared with heterozygous +/bg littermate controls. Human CH patients were compared with ageand sex-matched normal donors or unaffected siblings. Cytolytic assays were performed with tumor cells as targets. Data supporting this summary are referencedelsewhereSL ADCC: antibody-dependent-cell-mediated cytotoxicity; CTL: cytolytic T lymphocyte; MLC: mixed lymphocyte culture; ND: not done. bDoes not approach levelof interteron-boostednormal cells. cNot in all patients.

mice injected subcutaneously with a virally induced leukemia (P52) 33, a chemically i n d u c e d T-cell leukemia (EL-4), or B16 melanoma cells 34 had a higher incidence of tumor takes, a faster tumor induction time (shorter latency), increased tumor growthrate and, in the case of B16, an increased metastastic frequency. In particular, the n u m b e r of spontaneous pulmonary metastases of B16 from a primary subcutaneous tumor site was much greater in bg/bg than in +/bg control mice and the n u m b e r of lung colonies 15 days after intravenous inoculation of B16 cells was also greater 34. It is noteworthy that all the tumors used in these two studies (EL-4, P52, B16) were more sensitive to lysis by +/bg N K cells than by bg/bg N K cells in vitro. A n important control in these experiments was the observation that an NK-resistant variant of B16 was no different in growth and metastasis in bg/bg or +/bg mice. This rules out the possibility that beige mice have some u n k n o w n property, in addition to defective N K function, which might simply provide an enriched environment for the growth and spread of any tumor. Another control was the demonstration that after N K activity had been boosted with lymphocytic choriorneningitis virus tumor growth and metastasis was reduced in both normal and beige mice. Other investigators have reported a role for N K cells in the destruction of blood-borne, metastatic emboli of ultraviolet-light-induced fibrosarcomas3L Since longterm tumor growth experiments can be influenced by a variety of host factors in addition to NK, it was important in these experiments to look at short-term (4-18 h) tumor rejection in vioo using clearance of t25IUdR-labeled tumor cells as a measure of N K function 21. The experiments of Karre et al) 3 show more rapid clearance of tumors in +/bg than in bg/bg mice. Although all the above differences in tumor growth between bg/bg and +/bg mice were statistically significant and in the case of metastases sometimes profound, greater differences had been initially expected. Two explanations are readily apparent. First, the tumor-cell challenge itself greatly augments N K activity in both +/bg and bg/bg mice shortly (3 days) after injection33, probably by induction of interferon36 which greatly augments N K activity in vivo in both normaW and beige mice 38. Second, a challenge with a high dose of tumor cells overwhelms the putative N K surveillance mechanism in normal mice and no differences in tumor incidence are apparent, although latency and tumor growth are faster in bg/bg than in +/bg mice (Karre, unpublished observations). Since late endpoints are measured, it is even possible that the tumors appearing in normal mice could be NK-resistant variants which have successfully eluded the N K surveillance mechanism. These studies all rely on the inoculation of small numbers of experimental, transplantable tumors. It is not known how closely this method of tumor induction

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TABLE III. Tumor growth and metastasis in an NK-deficient mutant

Parameter measured Latency Incidence of takes Tumorsize Time to death Spontaneous pulmonary metastasis Lung colonies Clearance of 125IUdRlabeled cells In vitro NK activity (3 days) In vitro NK activity

Injection site

Tumor

s.c. s.c. s.c. s.c.

EL-4, EL-4, EL-4, EL-4,

P52, P52, P52, P52

s.c. i.v.

---

---

i.v.

--

P52

s.c. none

bg/bg

+/bg

B16 ~ Short B16 s High BI6 ~ Large - - Short

Long Low Small Long

B16 ~ Many None B16 ' Many None --

Slow Rapid

EL-4, P52 - - Low EL-4, P52, B16 ~ Low

High High

Data for the EL-4 and P52 leukemias are summarized from Karre et al. 33. The B16 ~melanoma data is from Talmadge, et al. 34. There were no differences between bg/bg and +/bg mice in the first five parameters when NK-resistant BI6 e" tumor cells were inoculated 34. B16~is an NK-sensitive line derived by prolonged (> 32 days) in vitro culture 34. The EL-4 and P52 tumors were maintained in vivo as ascites-passed lines 33. m i m i c s natural neoplasia in the host. R e c e n t studies of p r i m a r y t u m o r d e v e l o p m e n t in bg/bg mice reveal a higher incidence of t u m o r s after t r e a t m e n t with the e n v i r o n m e n t a l carcinogen, b e n z o [ a ] p y r e n e (Haliotis a n d Roder, u n p u b l i s h e d observations). In chickens, NK-like cells were shown to play a role in p r o t e c t i o n of adult birds against l e u k e m i a i n d u c t i o n by M a r e k ' s disease virus 39. F u r t h e r studies of this kind are clearly required.

Human studies A p r o f o u n d defect in N K activity in vitro recently has b e e n o b s e r v e d in a d u l t p a t i e n t s c a r r y i n g t h e a u t o s o m a l recessive gene causing C h e d i a k - H i g a s h i s y n d r o m e (analogous to the beige gene in mice) 4°. As in the mouse, this defect appears to be selective for N K cells since other i m m u n e functions ( T a b l e II) as well as cytolysis by monocytes, neutrophils a n d T cells are n o r m a l 40-43. T h i s study has now been e x p a n d e d to include an additional three patients (Roder, Haliotis, Boxer and M a t h e s o n , u n p u b l i s h e d results) all of w h o m exhibited a similar depression in N K function. If N K cells are i m p o r t a n t in t u m o r surveillance t h e n these patients should have a higher incidence of neoplasia. It is intriguing to note that the disease in 85% of the 53 C H cases on record entered an accelerated ' l y m p h o m a like' p h a s e 44, N K function is also depressed in patients with a variety of other i m m u n o d e f i c i e n c i e s < such as WiskottA l d r i c h syndrome, ataxia telangectasia and c o m b i n e d variable i m m u n o d e f i c i e n c y , and in kidney-allograft recipients on i m m u n o s u p p r e s s i v e t h e r a p y 46. In all

these types of patient there is a high incidence of m a l i g n a n c y 47 but since t h e y u n d o u b t e d l y also have several other i m m u n o l o g i c a l a b n o r m a l i t i e s one cannot ascertain the relative c o n t r i b u t i o n of N K cells alone to surveillance.

Remaining questions T h e stage is now set for a n u m b e r of critical experiments designed to test further the hypothesis that N K cells are i m p o r t a n t in surveillance against neoplasia. Are beige mutant m i c e m o r e s u s c e p t i b l e to spontaneous t u m o r s a n d t u m o r s induced by environm e n t a l carcinogens a n d oncogenic viruses? Are mice of n o r m a l strains m o r e susceptible to t u m o r s after in vivo depletion of N K ceils by a d m i n i s t r a t i o n of antibodies to a s i a l o - G M 1 a n t i g e n (an N K marker)48? Are t u m o r s w h i c h arise in beige mice m o r e susceptible to N K - m e d i a t e d cytolysis t h a n t u m o r s arising in n o r m a l controls? In n o r m a l a n i m a l s there is already evidence that m e t a s t a t i c t u m o r cells have a higher resistance to N K - c e l l - m e d i a t e d lysis t h a n do cells from the p r i m a r y tumor4L It will also be i m p o r t a n t to ask the question ' D o N K cells provide host resistance to all t u m o r s or is surveillance limited to t u m o r s of the l y m p h o i d s y s t e m ? ' and to d e t e r m i n e w h e t h e r or not t u m o r - b e a r i n g animals or h u m a n s can be p r o t e c t e d by a d m i n i s t r a tion of N K enhancers such as interferon.

Conclusions T h e study of N K cells has h a d several phases: it b e g a n with an u n e x p l a i n e d b a c k g r o u n d in conventional 'specific' assays, c o n t i n u e d with the definition of a p h e n o m e n o n m e d i a t e d by a discrete l y m p h o c y t e subclass a n d currently has b r o u g h t together c o m p e l l i n g evidence w h i c h suggests that N K cells play an i m p o r t a n t role in surveillance against e x p e r i m e n t a l and s o m e w h a t artificial t u m o r systems. N o w that selectively N K - d e f i c i e n t models are available in b o t h m a n a n d m o u s e it is i m p e r a t i v e that the role of N K cells in s p o n t a n e o u s t u m o r s is e x a m i n e d .

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Biliglobulin: a new look at IgA j. G. Hall and E. Andrew Block X, Institute of Cancer Research, Department of Turnout Immunology, Clifton Avenue, Sutton, Surrey, UK.

The teachings of Hippocrates and Galen ensured that physicians have always had a lively appreciation of the importance of bile, but somehow immunologists never got the message and hitherto they have paid it scant attention. Here Joe Hall and Liz Andrew discuss recent discoveries in Belgium and Britain which have shown that bile is a rich source of the secretory immunoglobulin IgA because the hepatocytes rapidly and actively transport this immunoglobulin from blood to bile. Not only are thesefindings important for understanding diseases involving the liver, the gut, immune complexes and tolerance to dietary antigens, but, in addition, they have provided research workers with an easy way of investigating secretory antibodies in small laboratory animals.

The beginning T h e ravages of enteric infections were a potent stimulus to the pioneer i m m u n o l o g i s t s of the final q u a r t e r of the n i n e t e e n t h century, who were well aware that b o t h the theory and practice of their science should be applicable to the gut. D u r i n g the 1920s specific agglutinins were d e m o n s t r a t e d in the © Elsevier/North-Holland Biomedical Press 1980

stools of patients with bacillary dysentery, and Besredka (a student and colleague of Elie M e t c h nikoff) showed that this disease could be p r e v e n t e d or m i n i m i z e d by an oral vaccine. T h e s e results were confirmed and e x t e n d e d by e x p e r i m e n t s in l a b o r a t o r y animals and livestock so that by the 1950s there was a substantial body of evidence that a special class of