Int. J . Cancer: 16,384-393 (1975)


Moshe GLASER l, Holger KIRCHNER and Ronald B. HERBERMAN Laboratory of Inimunodiagnosis, National Cancer Institute, Bethesda, Maryland 20014, U S A

WIFu rats were injected subcutaneously with low numbers of cells from the Gross leukemia virus-induced lymphoma, (C58N T ) D, which induced transient tumor growth and regression (regressors), or with high numbers of tumor cells resulting in progressive tumor growth (progressors) . Spleen cells from regressors had a significant reactivity in the mixed leukocyte tumor cell interaction ( M L T I ) , while spleen cells from progressors were unresponsive. Similarly, the responses to the non-specific mitogens, phytohernagglutinin and concanavalin A , were suppressed in spleen-cell cultures of progressors. Passage o f spleen cells from progressors over rayon adherence columns or pretreatment with an ironlmagnet technique resulted in almost complete restoration of M L TI and mitogen responses, Addition of spleen cells from progressors dcpressed the M LTI of spleen cells from regressors and the mitogen reactivity of normal spleen cells. Serum from progressors also suppressed ML T I and mitogen reactivity. These data indicate that, in spleens of rats bearing progressively growing tumors, suppressor cells can be demonstrated which inhibit specific reactivity to tumor-associated antigens and non-specific reactivity to mitogens. The presence of suppressor cells or of inhibitory factors in the serum may contribute to the immunosuppression frequently observed in tumor-bearing hosts.

Recent advances in tumor immunology have resulted from the observation that tumors possess specific antigens which can stimulate cell-mediated immune responses (for review see Herberman, 1974). However, most experimental tumors progress despite these cellular immune responses. Various reasons have been proposed to explain the lack of rejection of syngeneic tumors, and these include specific humoral blocking factors, such as antigen (Currie and Basham, 1972), antibody (Hellstrom

and Hellstrom, 1970), o r antigen-antibody complexes (Baldwin et a[., 1972). Non-specific humoral blocking factors may also exist (Glasgow et al., 1974a). I t has been shown that some in vitro lymphocyte functions of tumorbearing mice can be inhibited by suppressor cells which are found in spleens of such animals (Gorczynski, 1974; Kirchner et al., 1974a). In some tumor systems, specific cellular immunity has been detected in vitro during the early phase of tumor growth, but has disappeared

Received: May 20, 1975. Address reprint requests to: Moshe Glaser, Laboratory of Immunodiagnosis, National Cancer Institute, Building 8, Room 118, Bethesda, Maryland 20014, USA.



later during progressive tumor growth. This phenomenon has been designated " eclipse " (Youn et al., 1973). The mechanisms causing the eclipse of in vitro cellular immunity have not been understood. However, they may be of considerable importance for a better understanding of the in vivo immune unresponsiveness against the tumor. In the present study we have used a Gross leukemia virus-induced tumor system in the rat, in which humoral and cellular immunity to tumor-associated antigens have been extensively studied in our laboratory (Herberman and Oren, 1971 ; de Landazuri and Herberman, 1972). This tumor system has been also proven to be well suited for the demonstration of a mixed leukocyte tumor-cell interaction (MLTI) against mitomycin-C-treated syngeneic tumor cells. Spleen cells of rats immunized with low tumor doses, which led to regressing tumors, had a strong specific response in the MLTI, while spleen cells of rats bearing progressively growing tumors after inoculation of high tumor doses did not respond (Glaser et al., 1974). Evidence will be presented here that reactivity in the MLTI could be detected in rats with progressively growing tumors, but only after removal of suppressor cells by rayon adherence columns or by treatment with carbonylliron and a magnet. MATERIAL AND


Animals and tumors

Inbred W/Fu rats were obtained from the Mammalian Genetics and Animal Production Section, NIH, Bethesda, Md, USA. The Gross leukemia virus-induced rat lymphoma, (C58NT)D, (Geering et al., 1966) was maintained in ascitic form in weanling male W/Fu rats by serial intraperitoneal passage of 1 x lo' cells. Eight- to 10-week-old male W/Fu rats were inoculated subcutaneously into the right flank with 1 x lo8 tumor cells. This treatment caused transient tumor growth and regression within 2 weeks (Herberman and Oren, 1971). Subcutaneous inoculation of 1 x lo@tumor cells into rats of the same age resulted in progressive local tumor growth causing the death of the animals in 30-40 days. These two groups of animals will be subsequently designated " regressors " and '' progressors ", respectively.

Lymphocyte culture technique

Spleens were removed from progressors, regressors, or from normal control rats. Singlecell suspensions were prepared in medium RPMI 1640 supplemented with 100 yg/ml streptomycin, 100 IU/ml penicillin, 2 mM glutamine, and 5 % fetal bovine serum. This will subsequently be referred to as "medium". The technique of the MLTI has been previously described in detail (Glaser et al., 1974). Briefly, 6 x lo5 spleen cells and 2/104 (C58NT)D lymphoma cells treated with 25 ,ug/ml mitomycin-C (Sigma Chemicals Co., St. Louis, Mo., USA) were cultured in each well of tissue-culture-treated U plates (Cooke Laboratory Products, Cooke Engineering Co., Alexandria, Va., USA) at 37" C in an atmosphere of 5 % CO, and 95% air for 96 h. Controls consisted of spleen cells and tumor cells cultivated alone. For mitogen stimulation various doses of phytohemagglutinin PHA; Burroughs Wellcome, Research Triangle Park, N.C., USA) and concanavalin A (Con A; Calbiochem, San Diego, Ca., USA) were used and the cultures terminated at 72 h. Thymidine-methyL3H (3H-TdR; Schwarz Mann, Orangeburg, N.Y., USA; spec. act. 6 Ci/mmole, 1 yCi/well of the microplate) was added for the final 16 h of incubation and the cells were harvested on glass fibers using a multiple automated sample harvester (Microbiological Associates Inc., Bethesda, Md., USA). Radioactivity was determined in a liquid scintillation counter and results were expressed as mean counts per minute of triplicate samples (CPM). Pooled results from 3-5 experiments are given. Suppressor cell activity was demonstrated by adding various numbers of spleen cells from progressors to a fixed number (6 x lo5) of spleen cells from regressors or from normal rats. For demonstration of serum-mediated inhibitory effects, serum was collected from progressors, heat-inactivated at 56" C for 30 min and added at various concentrations to the spleen-cell cultures. Treatment of spleen cells by rayon adherence columns and by the ironlmagnet technique

These techniques have been described elsewhere (Kirchner et al., 1974a). Two large-sized rayon balls (Parke and Davis Co., Detroit, Mich., USA) were packed into 12ml syringes. These were autoclaved and washed with balanced



salt solution. About 1 x lo8 spleen cells in 6 ml of medium were incubated for 20min on the columns and then slowly eluted with 20ml of medium. About 30% of the initial cell population was recovered from the columns, and more than 98 % of the eluted cells were small lymphocytes. Lymphocyte separating agent, containing carbonyl iron particles, was obtained from Technicon Instruments Co., Tarrytown, N.Y., USA. 1 x lo8 spleen cells were suspended in 10 ml of this reagent and incubated for 60 min at 37°C in conical 50ml tubes. These were then put on top of a magnet and the supernatants recovered by Pasteur pipettes. This procedure was repeated 6-8 times and the cells were washed once before cultivation. This technique removed about 30% of the total cell population and eliminated the large majority of phagocytic cells as assessed by latex particle ingestion. RESULTS

Relationship between tumor growth and lymphocyte proliferative responses

W/Fu rats injected with 1 x lo9 (C58NT)D tumor cells developed 100% progressively growing tumors which usually caused the death of the animals between 30 and 40 days. Spleens of these rats were considerably enlarged and at 30 days contained 3-4 times the number of mononuclear cells of normal W/Fu rat spleens. The percentage of macrophages as determined

by the uptake of latex particles was also increased in spleens of tumor-bearing rats (9.3% as compared to 3.4% in spleens of normal rats). Morphologically, no evidence was obtained for the presence of significant numbers of tumor cells in these spleens. No proliferative response to (C58NT)D tumor cells was seen at any time after inoculation of 1 x loQtumor cells (Fig. 1). However, spleens of regressors demonstrated significant reactivity in the MLTI between 20 and 40 days after injection of (C58NT)D. A significant depression of mitogen reactivity to PHA and Con A was first noted at 20 days in progressors (Fig. 2). At 30 days mitogen reactivity was more than 80 % depressed when compared to normal control spleen cell cultures. This depression could not be overcome by increasing the mitogen doses in culture. Spleen cells from regressors had normal reactivity to these mitogens during the entire period of tumor growth and regression (data not shown). Restoration of MLTI and mitogen reactivity of spleen cells from progressors

Spleen cells from rats inoculated with 1 x loQ (C58NT)D tumor cells, which did not react in the MLTI, revealed significant reactivity after pretreatment with rayon adherence columns or an iron/magnet technique (Table I). These procedures also led to some increase in MLTI reactivity of spleen cells from regressors.

10 -



2 -









MLTI of spleen cells from regressors (0)or from progressors (0)tested at various times after inoculation of (C58NT)D tumor cells. The results are expressed as the mean CPM of triplicate cultures.










\ 30










Stimulation of spleen cells from progressors by PHA (a) or Con A (0) at various times after inoculation of 1 x lo8 (C58NT)D tumor cells. Tunior growth is also shown (0).

However, there was no reactivity of normal spleen cells after these procedures. Similar results were obtained when mitogen reactivity of spleen cells was compared before and after purification (Table 11). Reactivity of spleen cells from progressors to high and low doses of PHA and Con A was significantly increased after column treatment and treatment by the ironlmagnet technique. Normal spleen cells showed a markedly depressed response at higher doses of PHA and Con A. This depression was also reversed by the purification procedures. TABLE I RESTORATION OF MLTI OF SPLEEN CELLS



None Rayon adherence columns Iron/magnet None Rayon adherence columns Iron/magnet



2,217 2,158

9,257 8,588



2,227 2,008

7,915 7,085


Mixture of mitornycin C-treated (C58NT)D cells with spleen cells. Mean CPM of triplicate cultures.

At lower, optimal doses of mitogens, these treatments had little effect on the responses of normal spleen cells. Inhibition of MLTI and mitogen responses by spleen cells from progressors

The above experiments suggested a possible role of suppressor cells in the inhibition of the specific and non-specific proliferative responses, and the following experiments were performed to examine this possibility. Spleen cells from progressors were mixed at various proportions with spleen cells from regressors or from normal rats. To control cultures, spleen cells from normal rats were added. The MLTI of regressors was completely inhibited by addition of as few as 15% of spleen cells from progressors (Fig. 3). No inhibition was seen by addition of the same number of normal spleen cells. Similarly, the mitogen responses in spleen-cell cultures from normal rats were markedly inhibited by addition of spleen cells from progressors (Fig. 4). Increasing the cell density in these cultures by the same number of normal spleen cells had only a minimal inhibitory effect. The suppressive capacity of spleen cells from progressors was abrogated after passage of the cells through adherence columns or by pretreatment with





Con A


2.5 pg/ml


2.5 r g / r n l

10 v d m l

Normal rats

None Rayon adherence columns Iron/magnet

1,383 2,732 2,611

42,898 67,382 64,251

10,583 71,394 69,801

67,416 85,271 81,200

20,012 89,024 85,921


None Rayon adherence columns Iron /magnet

2,507 2,227 2,008

14,606 69,516 65,718

7,212 73,819 70,953

18,920 88,217 85,207

9,102 92,716 89,007

' Mean CPM of triplicate cultures.

the iron/magnet technique (data not shown). Spleen cells from regressors during the entire period of tumor growth and regression had no inhibitory effect (data not shown). Inhibition of' MLTI and mitogen reactivity by serum from progressors

Serum from progressors, collected 30 days after tumor-cell inoculation, o r from normal


control rats, was added in various concentrations to spleen-cell cultures of regressors o r of normal rats. A marked inhibition of the MLTI was noted by addition of 5 % serum from progressors (Table III), while the same concentration of normal rat serum had no inhibitory effect. Similarly, the mitogen responses were strongly suppressed by 5-10 % serum from progressors (Table IV) while normal rat serum had little

Spleen cells from normal rats


P I-


8 a

8 z c3



T 3


2t 0' 0

rn Spleen cells from progressors



I 20



PERCENTAGE OF CELLS ADDED TO SPLEEN CELLS FROM REGRESSORS FIGURE 3 Inhibition of MLTI by spleen cells from progressors. To a mixture of spleen cells from regressors and (C58NT)D cells, varying proportions of spleen cells from progressors (A) or from normal rat ( A ) were added.





Spleen cells from normal rats ---*---






+ t

‘O0 0







FIGURE 4 Inhibition of Con A response by spleen cells from progressors. To a standard mixture of normal spleen cells and 2.5pg/ml Con A were added additional normal spleen cells ( A ) or spleen cells from progressors (A).

or no effect on the mitogen responses. Serum from regressors during the entire period of tumor growth and regression had no inhibitory effect (data not shown).


None 10% normal rat serum 5%

2.5% 1.25 %

10% serum from progressors 5% ” ”

2.5% 1.25%

Spleen cells alone

2,275 1,789 1,884 2,072 2,101 1,188 1,571 1,539 1,750


7,321 6,130 6,773 8,323 7,914 1,955 3,781 7,988 7,652


‘ Mixture of mitomycin Gtreated (CS8NT)D cells with spleen cells from regressors. Mean CPM of triplicate cultures of spleen cells from regressors. a Final concentration of serum in cultures.


In the present study it was demonstrated that specific reactivity, of spleen cells from rats bearing progressively growing tumors, to (C58NT)D tumor cells in the MLTI was not detectable and that the responses to nonspecific mitogens were strongly depressed. Pretreatment of the spleen cells by rayon adherence columns and by an iron/magnet technique reversed these defects. Furthermore, in mixture experiments, where spleen cells from progressors were mixed with spleen cells from regressors o r from normal rats, a strong inhibitory effect was seen. This suppression appeared not to be a tissue-culture artefact since increasing the cell density by an equal number of normal spleen cells had little or no inhibitory effect. These studies indicate that suppressor cells are present in the spleens of rats with progressively growing tumors, inhibiting the proliferative responses of lymphocytes. These suppressor cells apparently acted non-specifically since they inhibited the responses to mitogens as well as to tumor-associated antigens.



None 10% c 01


normal rat serum ,. ,, 91


serum from progressors 5 % serum from progressors 2.5 % serum from progressors 1.25 ”/, serum from progressors



Con A ‘

2,351 1,853 1,945 2,118 2,278

40,980 35,201 48,351 51,810 52,322

62,321 57,601 76,553 81,510 86,I70






1 1,825 32,734


41,076 80,855


49,327 90,933

Mean CPM of triplicate cultures of normal spleen cells. Final concentrations of serum in culture. 2.5 pg/ml of PHA. 2.5 pg/ml of Con A .

The present data have to be discussed in the context of two previous series of experiments. Folch and Waksman (1973a, 6 ) have demonstrated suppressor cells in spleens of normal rats which inhibited mitogen responses at higher than optimal mitogen doses. The same phenomenon was also observed in our study, since the depressed responses of normal spleen cells to PHA and Con A at concentrations of 10pg/ml were substantially increased after treatment with adherence columns and by an ironlmagnet technique. In contrast to the findings obtained with normal spleen cells, reactivity of spleen cells from rats with progressively growing tumors were depressed even at doses optimal for normal spleen cells. Subsequently, Waksman and his co-workers have presented evidence that the splenic suppressor cell is an adherent cell, which is different from macrophages, and that the suppressor activity is T-cell-dependent, and even perhaps may be mediated by a T-cell (Yoshinaga et al., 1972; Folch and Waksman, 19736). Our studies in the tumor system have not yet been as extensive as those studies. It therefore still remains to be established whether the type of suppressor cell inhibiting reactivity

3 90

of normal spleen cells at higher than optimal mitogen doses is identical with the one we are observing in spleens of rats bearing progressively growing tumors. Our data obtained with the carbonyl iron technique suggest that the suppressor cells in our system are macrophages. However, this technique, as well as the rayon columns, removes other cells in addition to macrophages. Extensive studies in our laboratory have previously established the presence of suppressor cells in spleens of tumor-bearing mice (Kirchner et a/., 1974a, b, 1975). In mice, suppressor cell activity was not dependent on T-cells since activity was not abrogated by treatment with anti-theta serum plus complement. Suppressor cells were also found in spleens of tumor-bearing nude mice, which contain few if any functional T-cells. The suppressor cells also appeared not to be B-lymphocytes since they were not removed by antigamma globulin immunoabsorbent columns. In contrast, as in the present study, various methods which removed macrophages were able to abolish the suppressive capacity of spleen cells from tumor-bearing mice. Furthermore, similar data were reported in mice after injection of killed Corynebacterium parvum (Scott, 1972). By analogy, therefore, it appears likely that the suppressor cells in the rat tumor system are also macrophages, but further work is necessary to firmly establish this. The most important aspect of this study is the demonstration that the splenic suppressor cells inhibited reactivity to tumor-associated antigens as well as to mitogens. Thus, we have shown that spleen cells from progressor rats which previously appeared to lack cells reactive in the MLTI gave positive responses after removal of the suppressor cells. In several tests, including the MLTI, an “eclipse” of in vitro cellular immunity has been reported after the tumor reached a certain critical size (Youn et al., 1973; Lopez et al., 1974; Burk et al., 1975). Our data indicate that the apparent eclipse of the MLTI was due to suppressor cells and it is possible that such cells play a role in the eclipse phenomena associated with other assays of cellular immunity. In the Moloney sarcoma virus (MSV) system of the mouse, a good correlation was observed between the growth pattern of the tumor and the development of the suppressor cells. Thus,


no suppression was seen before the tumor had reached an appreciable size, and suppression of mitogen reactivity was reversed after regression of the tumor. Similarly, in mice bearing progressively growing methylcholanthrene-induced tumors (Kirchner et al., 19746) and in the rat system studied here, there was quite a long period of progressive tumor growth before suppressor cell activity could be detected. This suggests that activation of suppressor cells may be mediated by substances released from the tumor, which only reach sufficient levels after the tumor has attained a certain size. In the MSV system, suppressor cells could be detected in both progressors and regressors during the time of maximal tumor growth (Kirchner et al., 1974a), while in the (C58NT)D system suppressor cells were only found in spleens of progressors. The reason for this difference may be that in the MSV system tumors reach a large size before they start to regress, while regressing (C58NT)D tumors are quite small in relation to the body weight of the rats. In this study it was also shown that serum from progressor rats had a strong inhibitory effect on the in vitro proliferative responses of spleen cells. The mechanisms of this inhibition and the components of the serum mediating this inhibition are not clear. Previous studies in our laboratory have shown that (C58NT)D tumor cells release material of a macromolecular nature which inhibits the proliferation of lympho-

cytes (Bonnard and Herberman, 1975). It is conceivable that the inhibitory material in the serum is of tumor origin. Exposure of the spleen cells to these substances may then result in activation of the suppressor cells. It should be emphasized that the inhibitory effect of sera seen here was non-specific, inhibiting mitogen responses as well as the MLTI. This appears to be different from the specific serum blocking factors previously described in microcytotoxicity assays (Hellstrom et al., 1971) or in the MLTI with some human tumors (Vanky et al., 1973). Our data are similar to previous work from other laboratories, where non-specific inhibition of mitogen stimulation by serum from cancer patients has been shown (Sample et al., 1971; Silk, 1967). Immunosuppressive alphaglobulin which has been shown to suppress non-specific mitogen reactivity (Glasgow et a/,. 1974a, 6) and reactivity in the MLTI (Glaser and Herberman, 1974) may also play a role in the inhibition by serum from progressors. Our data indicate that suppressor cells and humoral factors may both play a role in the non-specific immunosuppression caused by a tumor and in the immune unresponsiveness against the tumor itself. However, the effects have thus far only been demonstrated in vitro. It will be important to determine whether suppressor cells or inhibitory serum factors play a role in vivo, by interfering with effective host resistance against tumor growth.

INHIBITION DES REPONSES LYMPHOPRO LIFERATIVES I N VITRO CONTRE LES ANTIGENES ASSOCIES A LA TUMEUR PAR DES CELLULES A EFFET SUPPRESSEUR PROVENANT DE RATS PORTANT DES TUMEURS INDUITES PAR LE VIRUS DE LA LEUCEMIE DE GROSS Q U l EVOLUENT PROGRESSIVEMENT Des rats WIFu ont r e p des injections sous-cutantes de cellules d’un lymphome induit par le virus de la leuctmie de Gross, (C54 NT) D; un pet it nombre de ces cellules a induit une tumeur qui a tvolut pendant un certain temps puis rtgresst (rkgresseurs), alors que l’injection d’un grand nombre de cel lules tumorales a entrain6 un dtveloppement progress$ de la tumeur (progresseurs). Les cellules sple‘niques des rtgresseurs ont rtagi de facon significative lors du test d’interac tion mixte leucocytes-ceNules tumorales (MLTI) alors que celles des progresseurs n’ont pas rtagi. De mime, les rtponses aux mitogenes non spe‘cifques, la phytohtrnagglutinine et la concanavaline A , ktaient nulles dans les cultirres de cellules splkniques des prog resseurs. Le passage de ces dernikres sur des colonties de rayonne ou le prttraiternen t selon la technique ferlaimant a rktabli presque


totalement la M L T l et ies rkponses aux mitogenes. L’addition de cellules spleniques de progresseirrs a fait diminuer la M L TI des cellules spltniques de rPgresseurs ainsi que la reponse des cellules spltniques normales aux mitogenes. Le strum de progressenrs a kgalement supprimt la M L TI et la reaction aux mitogenes. Ces consfatations indiquent que, dans la rate des rats portant des tumeurs Cvoluant progressivement, on peut rnettre en Pvidence des cellules ci e f e t suppresseur qui inhibent la riactivitk spkcifique contre les antigenes associPs a la tumeur et la rPactivitC non spbcifique a I’Pgard des mitogenes. La prisence de ces cellules ou de facteurs inhibiteurs dans le strum peut contribuer a I’immunosuppression que I’on’ observe frPquemment chez les hBtes canctreux.


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Inhibition of in vitro lymphoproliferative responses to tumor-associated antigens by suppressor cells from rats bearing progressively growing Gross leukemia virus-induced tumors.

W/Fu rats were injected subcutaneously with low numbers of cells from the Gross leukemia virus-induced lymphoma, (C58NT)D, which induced transient tum...
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