SUBVERSION OF HOST DEFENSE MECHANISMS
BY MURINE TUMORS
II. Counter-Influence of Concomitant Antitumor Immunity*
BY ROBERT J. NORTH, DAVID P. KIRSTEIN, AND RICHARD L. TUTTLE
It was shown in the preceding paper (1) t h a t subcutaneous injection of cells of any one
of five unselected m u r i n e tumors resulted within 24 h in the presence of a factor in
circulation t h a t severely suppressed the ability of mice to resist experimental infection
with Listeria monocytogenes and Yersinia enterocolitica. It was suggested, on the basis of
the knowledge (2) t h a t both native and acquired resistance to Listeria infection are
expressed by macrophages, t h a t the tumor-suppressor factor exerted its effect by either
directly or indirectly interfering with the function of these phagocytic cells. It was
suggested, in turn, t h a t the evidence is consistent with the proposition that at least some
m a l i g n a n t cells are n a t u r a l l y selected to avoid destruction by a macrophage-mediated
mechanism of native a n t i t u m o r resistance. Obviously, this view would have more credence if it were shown t h a t mice with suppressed antibacterial resistance displayed at the
same time a reduced capacity to resist the growth of a challenge of tumor cells.
Again, the preceding paper only dealt with the events t h a t i m m e d i a t e l y followed
injection of t r a n s p l a n t a b l e tumor cells. It remained a possibility, therefore, t h a t suppression of antibacterial resistance is only a short-term effect of tumor cell implantation.
Indeed, this could be suggested on the grounds t h a t it is by no means a commonly
reported finding t h a t d e a t h from acute n a t u r a l infection is a consequence of injecting
experimental animals with tumor cells. On the contrary, there is a recent demonstration
(3) t h a t mice b e a r i n g the Lewis lung carcinoma display increased resistance to Candida
albicans infection.
T h e p u r p o s e of t h i s p a p e r is t o s h o w t h a t t h e s t a t e of s e v e r e l y i m p a i r e d
antibacterial resistance which immediately follows subcutaneous injection of
m u r i n e t u m o r c e l l s is s h o r t l i v e d , i n t h a t i t is s o o n r e p l a c e d b y a c o n t r a s t i n g
s t a t e of g r e a t l y i n c r e a s e d a n t i b a c t e r i a l r e s i s t a n c e ; i n s p i t e of t h e c o n t i n u o u s
p r e s e n c e of t h e s u p p r e s s o r f a c t o r i n c i r c u l a t i o n . E v i d e n c e w i l l be p r e s e n t e d to
show that the tumor-induced states of decreased and increased antibacterial
r e s i s t a n c e c o r r e s p o n d to s t a t e s of d e c r e a s e d a n d i n c r e a s e d r e s i s t a n c e t o t h e
t u m o r itself. C o n s e q u e n t l y , t h e r e s u l t s s u p p o r t t h e p r o p o s i t i o n t h a t a n t i b a c t e rial and antitumor resistance are expressed by a common defense mechanism.
Materials and Methods
The materials and methods employed were the same as those employed in the preceding paper
(1) except for additional procedures that were used to measure resistance to a tumor cell challenge.
Antitumor Resistance. Mice bearing a progressive subcutaneous tumor in the right-hind foot
pad were compared with normal control mice in terms of their capacity to resist the growth of
* This investigation was supported by grant no. CA-16642 awarded by the National Cancer
Institute, and by grant no. AI-10351 from the Institute of Allergy and Infectious Diseases,
Department of Health, Education, and Welfare.
574
THE JOURNAL OF EXPERIMENTAL MEDICINE • VOLUME 143, 1976
ROBERT J. NORTH, DAVID P. KIRSTEIN, AND RICHARD L. TUTTLE
575
either a subcutaneous or intraperitoneal challenge of tumor cells. Resistance to subcutaneous
tumor cell challenge at progressive times during growth of the primary tumor was determined by
measuring the growth of a standard n u m b e r of tumor cells injected into the contralateral foot pad.
The cells were injected in a vol of 0.05 ml of phosphate-buffered saline (PBS), j and tumor growth
was monitored by m e a s u r i n g changes in the dorso-ventral thickness of the foot pad with dial
calipers.
Changes in resistance to growth of an intraperitoneal challenge of tumor cells was determined
by measuring changes in the quantity of tritiated thymidine ([3H]TdR) incorporated into total
peritoneal cell DNA according to a published method (4). This involved challenging mice intraperitoneally with a standard dose of tumor cells in a vol of 0.2 ml of PBS at progressive times during
the growth of the primary subcutaneous tumor. At 24-h intervals over the next 3 days the mice
were given a single intravenous pulse of 20 /iCi [3H]TdR of sp act 3 Ci/mmol (New England
Nuclear, Boston, Mass.). 30 min later, the peritoneal cells were harvested in 3 ml of heparinized
PBS in a standard fashion, washed two times over a period of 1 h in ice-cold 5% TCA, and then
extracted for 1 h in 2 ml of hot (90°C) TCA. 3H-DNA in the extract was counted by liquid
scintillation spectrometry.
Results
Conversion from Suppressed to Enhanced Antibacterial Resistance during
Tumor Growth. The preceding paper showed (1) that subcutaneous injection of
tumor cells resulted in rapid suppression of resistance to intravenous Listeria
infection. The following experiments were designed to determine whether this
state of severely suppressed antibacterial resistance persists during subsequent
growth of the primary tumor. The experiment consisted of injecting semisyngeneic mice subcutaneously with 106 SA1, P-815 mastocytoma, or Meth A cells,
and measuring the capacity of the mice at progressive times thereafter to resist
a standard 5 × 103 intravenous Listeria challenge infection. Antibacterial
resistance was expressed as the loglo difference between the growth of the
challenge organism in the livers of tumor-bearing mice and its growth in livers
of control mice at 24 h of infection.
The results in Fig. 1 reveal, in agreement with those in the preceding study,
that subcutaneous injection of tumor cells quickly resulted in a state of severely
suppressed antibacterial resistance. It can be seen in addition, however, that the
state of negative resistance rapidly waned after 24 h, and was soon replaced by a
contrasting state of greatly increased antibacterial resistance. The speed at
which this conversion from suppressed to enhanced antibacterial resistance
occurred, moreover, was related to the rate of growth of the primary tumor. The
experiments were terminated when the condition of the mice had deteriorated
because of the massiveness of the primary tumors.
To exclude the possibility that conversion from negative to positive antibacterial resistance was the unlikely result of a nonimmunological response of the F1
hybrid against parental tumor cells, the same experiment was performed with
syngeneic mice. That syngeneic A/J mice injected with 106 SA1 cells gave the
same results is shown in Fig. 2.
Comparison between States of Negative and Positive Antibacterial Resistance. The meaning, in terms of overall resistance to infection, of the states of
negative and positive resistance as revealed by the 24-h growth assay shown
1Abbreviations
saline.
u s e d in t h i s p a p e r :
[3H]TdR, tritiated thymidine; PBS, phosphate-buffered
576
SUBVERSION
OF
HOST
DEFENSE
MECHANISMS.
II
15I0-
-7
05-
-6
0-
-5
-4
-3
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-10-
-2
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,ic
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FIG. 1. Changes in resistance to Listeria infection (bar graphs) during growth of three
murine tumors in semisyngeneic mice. Subcutaneous implantation of tumor cells first
resulted in a state of severely suppressed resistance and then in a contrasting state of
enhanced resistance. Resistance is expressed as the loglo difference between the 24-h growth
of the organism in livers of control and tumor-implanted mice. Means of five mice per time
point.
above is more convincingly demonstrated in Fig. 3, which compares the 2-day
growth of Listeria in the livers of 1-day and 9-day tumor bearers. It can be seen
that whereas a 2 x 103 Listeria inoculum showed enhanced growth for 2 days in
the livers of 1-day tumor bearers, no bacterial growth occurred in the livers of 9day tumor bearers. Thus while 1-day tumor bearers were highly susceptible to
infection, 9-day tumor bearers were highly resistant.
Presence of Suppressor Factor in Circulation in Spite of Acquisition of Enhanced Antibacterial Resistance. It is known (1) that the short-term state of
suppressed antibacterial resistance that rapidly follows injection of tumor cells
is mediated by a small molecular weight factor in circulation. To determine
whether the production of this molecule continues in spite of the change from
suppressed to enhanced antibacterial resistance, an experiment was performed
to test for its presence in serum during a 9 day period of tumor growth. Thus,
serum obtained from (AB6)F1 donor mice at progressive intervals after initiating a subcutaneous tumor with 106 SA1 cells was tested for its capacity to
ROBERT
J.
NORTH,
DAVID
P. K I R S T E I N ,
AND
RICHARD
L. T U T T L E
577
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Same experiment as Fig. 1, but in syngeneic mice.
FzG. 2.
7'~
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DAY9
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FIG. 3. Additional evidence for conversion from suppressed to enhanced antibacterial
resistance during subcutaneous growth of an SA1 tumor. The liver growth curves show that
whereas 1-day tumor bearers allowed enhanced growth of a sublethal Listeria challenge for
a 2 day period, 9-day tumor bearers were highly resistant to the same challenge. Means ± 2
SE of five mice per time point.
suppress anti-Listeria resistance w h e n infused into n o r m a l recipients. S e r u m
w a s injected intraperitoneally in a vol of 0.2 ml 1 h before i n t r a v e n o u s c h a l l e n g e
with 2 × 10 ~ Listeria. Bacterial growth w a s m e a s u r e d by t h e 24-h g r o w t h a s s a y
e m p l o y e d in a preceding section.
Fig. 4 s h o w s that an infusion of 0.2 ml of s e r u m collected at a n y t i m e during
growth of t h e primary t u m o r w a s able to significantly suppress the antibacterial
resistance of n o r m a l recipients. It will be noted, h o w e v e r , that there w a s a drop
in the potency of the s e r u m after about the 5th day of t u m o r growth, i.e., after
the conversion from n e g a t i v e to positive antibacterial resistance (Fig. 1). Indeed, the resuts of a l i m i t i n g dilution a s s a y e m p l o y e d in t h e preceding paper (1)
indicate that this drop m a y h a v e represented as m u c h as a 50-fold reduction in
concentration of the suppressor factor.
N e v e r t h e l e s s , w h e n sera from 1-day t u m o r - b e a r i n g donors and 9-day tumorbearing donors were compared in t e r m s of their capacity to increase bacterial
growth in t h e livers of n o r m a l recipients over a 3 day period, it w a s found (Fig. 5)
578
SUBVERSION OF HOST DEFENSE MECHANISMS. II
w 0.5r.~
_o
0
-05-
IIII I'
-1.0-
$AI in (A65) FI
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i
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FIo. 4. Evidence that a suppressor factor persisted in circulation for at least 9 days of
tumor growth. An intraperitoneal infusion of 0.2 ml of tumor-bearers' serum collected at
any of the times indicated after implanting tumor cells, suppressed the capacity of normal
recipients to resist sublethal Listeria infection. Means of five mice per time point.
77
OAY !
5-
/ -
DAY 9
i
-
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Fro. 5. Additional evidence that 9-day tumor bearers contained a suppressor factor in
circulation. A 0.2 ml infusion of 9-day as well as 1-day tumor-bearers' serum caused
continuous bacterial growth for 3 days in the livers of normal recipients. Means -+ SE of five
mice per time point.
that 0.2 ml of 9-day serum as well as 0.2 ml of 1-day serum caused enhanced
bacterial growth over this period. It can be concluded, therefore, that in spite of
conversion from a state of negative to a state of highly positive antibacterial
resistance, a suppressor of antibacterial resistance persisted in circulation.
Failure of Allogeneic and Lethally Irradiated T u m o r Cells to Cause Enhanced Antibacterial Resistance. It was important for the design of future
experiments to know whether the suppressed antibacterial resistance which
results from subcutaneous injection of lethally irradiated tumor cells or of
allogeneic tumor cells (1) is also followed by a state of enhanced antibacterial
resistance. The possibility that increased bacterial resistance might fail to
develop is suggested by the knowledge that lethally irradiated tumor cells cause
no tumor growth, and that aUogeneic tumor cells result in only a limited period
of tumor growth. This question was investigated by an experiment that involved
measuring changes against time in resistance to a Listeria challenge infection of
(AB6)F~ mice that were injected subcutaneously with either 10s lethally irradi-
ROBERT J. NORTH, DAVID P. KIRSTEIN~ AND RICHARD L. TUTTLE
579
0.S.
0
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Fro. 6. Evidence that implantation of lethally irradiated or allogeneic tumor cells failed
to result in the generation of a state of increased antibacterial resistance. In both cases, the
state of severely suppressed resistance to a Listeria challenge that occurred after implantation of tumor cells was followed by a return to normal levels of antibacterial resistance.
Means of five mice per time point.
ated SA1 cells as a semisyngeneic tumor, or with 106 Meth A cells as a n
allogeneic tumor. Changes in anti-Listeria resistance were m e a s u r e d by the 24h growth assay described above.
It was found (Fig. 6) t h a t a l t h o u g h lethally i r r a d i a t e d t u m o r cells caused a
short-lived state of suppressed antibacterial resistance, there was no s u b s e q u e n t
conversion to a state of increased antibacterial resistance. Instead, the level of
antibacterial resistance r e t u r n e d to normal by day 5. Fig. 6 shows t h a t a similar
result was obtained with a n allogeneic tumor, the early rejection of which was
associated with a r e t u r n to a normal level of antibacterial resistance. T a k e n
together, these results indicate t h a t the g e n e r a t i o n of a state of increased
antibacterial resistance depends on progressive growth of the p r i m a r y tumor.
Changes in Antibacterial Resistance Reflect Changes in Resistance to the
T u m o r Itself. The e x p e r i m e n t s presented in this section were designed to test
the prediction t h a t changes in the level of antibacterial resistance t h a t occur
d u r i n g growth of a p r i m a r y t u m o r are the result of changes in the level of host
resistance to the t u m o r itself. This prediction was tested by injecting (AB6)F~
mice subcutaneously in the right-hind foot pad with 106 SA1 cells, and measuring t h e i r capacity at progressive times t h e r e a f t e r to resist the growth of a
challenge of 5 × l0 S t u m o r cells given either subcutaneously in the c o n t r a l a t e r a l
foot pad, or intraperitoneally.
The results obtained with the subcutaneous challenge are shown in Fig. 7
where it can be seen t h a t initiation of a subcutaneous p r i m a r y t u m o r first
resulted in a short-term state of suppressed resistance as evidenced by "enhanced growth" of a challenge given on day 3, and t h e n in a contrasting state of
greatly increased resistance as evidenced by a striking suppression of growth of
the same challenge given on days 6 or 9. T h e t i m i n g of the change from
suppressed to enhanced a n t i t u m o r resistance t h u s shows a striking concordance
with the change from suppressed to enhanced antibacterial resistance (Fig. 1).
SUBVERSION
580
OF HOST DEFENSE M E C H A N I S M S .
II
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/
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15'
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10"
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15'
10'
I°
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I
OAYS OF PRIMARYTUMOR GROWTH
Evidence that s u b c u t a n e o u s implantation of 10 '~ SA1 cells first resulted in a state
of suppressed resistance ("enhanced growth") to a subcutaneous 10 '~ challenege of tumor
cells, and t h e n in a contrasting state of increased resistance to a challenge of the same cells.
Means of five mice per time point.
FIG. 7.
The same time relationship was found when the peritoneal cavity was used to
test for antitumor resistance. It can be seen in Fig. 8 that whereas the period
that immediately followed initiation of the primary subcutaneous tumor was
characterized by a state of greatly reduced resistance to growth of the intraperitoneal tumor cell challenge Cenhanced" [3H]TdR incorporation), this was soon
followed by the development of a powerful mechanism of resistance to the same
challenge (suppressed [3H]TdR incorporation). Differences between the control
and experimental groups on day 3 of the assay are plotted at the bottom of Fig. 8
to show more clearly the time-course of conversion from suppressed to enhanced
resistance.
ROBERT J.
NORTH,
D A V I D P.
KIRSTEIN,
AND RICHARD
L. T U T T L E
581
o T-I
24'
/
20'
b CONTROL
16"
7
~]2"
~, T*4
• 1-2
f
g
,s T*6
8-
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4"
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n-n
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7
9
12
UAYS OF l ° TUMOR AT TIME OF ASSAY
lq
FZG. 8. Conversion from negative to positive resistance to an intraperitoneal tumor cell
challenge. The 3-day [3H]TdR incorporation curves (top graph) show that an intraperitoneal
challenge of tumor cells underwent "enhanced growth" (increased [3H]TdR incorporation)
when injectedeither at the time of, or I day afterinitiatinga subcutaneous primary tumor.
In contrast,growth of the same challenge was suppressed (decreased [3H]TdR incorporation)
when given at later times. The bar graph plots the 3-day differencesin [3H]TdR incorporation between tumor-bearing and control mice in order to better illustrateconversion from
suppressed to enhanced antitumor resistance. Means of five mice per time point.
It will be noted that the switch from negative to positive antitumor resistance
occurred faster according to the peritoneal assay. It should be pointed out,
however, that additional experiments have revealed that the speed at which the
switch occurs depends on the number of tumor cells used to initiate the primary
tumor and the number used for challenge.
Discussion
The results of this study confirm those of the preceding study (1) which showed
that subcutaneous injection of murine tumor cells results in rapid and severe
suppression of the capacity of mice to resist experimental infection with the
bacterial parasite, L. monocytogenes. The present results show, in addition, that
the tumor-induced state of suppressed antibacterial resistance was short lived
and was soon replaced by a contrasting state of greatly enhanced antibacterial
resistance. Again, conversion from suppressed to enhanced resistance was
shown to depend upon progressive growth of the primary tumor, and to correspond with conversion from suppressed to enhanced resistance to growth of a
tumor cell challenge. The results show, therefore, that changes in the level of
582
SUBVERSION OF HOST DEFENSE, M E C H A N I S M S .
II
antibacterial resistance reflect changes in the level of resistance to the tumor
itself. This implies that antibacterial resistance and antitumor resistance are
expressed by a common mechanism of defense.
The generation of the capacity to strikingly resist the growth of a tumor cell
challenge during rapid growth of the primary tumor means that the host
generated a state of concomitant antitumor immunity (5), the nature of which
will be dealt with in a forthcoming publication. It can be suggested here,
however, that because it appeared coincidentally with the development of
macrophage-mediated anti-Listeria resistance, it is almost certain that concomitant immunity itself is expressed by activated macrophages. This seems a
reasonable suggestion in view of the large body of evidence which shows (6-8)
that macrophages activated in vivo as a result of microbial infection can recognize and destroy neoplastic cells in a nonimmunological way in vitro. The
suggestion is also supported by earlier in vivo findings (9) which showed that
animals with macrophage systems activated as a result of treatment with
infectious and noninfectious agents acquire the capacity to retard the growth of
a tumor cell challenge. The results of this paper show that the converse is true in
that the response to the tumor itself results in the generation of an activated
macrophage system. In fact, the results suggest that the level of nonspecific
macrophage-mediated antibacterial resistance eventually generated in response
to the SA1 sarcoma is at least equal to, or even higher than the level of
nonspecific antibacterial resistance generated in response to an intravenous
BCG infection. This is in keeping with publications which show that tumorbearing humans (10) as well as tumor-bearing animals (9) can show an increased
capacity to clear intravenously injected colloids from their circulation.
The present study lends more credence to the view that activated macrophages play an important role in antitumor defense. More direct evidence to
suggest that concomitant antitumor immunity is expressed by macrophages,
and that it can therefore be expressed nonspecifically against antigenically
unrelated tumors, has recently been reported (11). Our findings serve to emphasize the nonspecific nature of the resistance since they clearly show that it is
expressed against infectious agents. It is not surprising, therefore, that in spite
of an initial state of severely suppressed antibacterial resistance, death from
acute natural infection is not a commonly reported consequence of injecting
experimental animals with syngeneic tumor cells.
The coincident development of a state of increased antitumor and antibacterial resistance is not the only reason for postulating a common mechanism of
defense against microorganisms and neoplasia. The postulate is also supported
by the finding that resistance to both agents is simultaneously suppressed after
initiating a primary tumor. In this case, however, a native mechanism of
resistance is involved. Indeed, it is difficult to escape the conclusion that an
initial implant of tumor cells survives and grows because of its capacity to
rapidly suppress a native defense mechanism that would otherwise cause its
destruction. Since the only cells in the mouse that can destroy Listeria are
macrophages, it seems likely that the suppressor factor described in the preceding paper (1) serves to protect the primary tumor from destruction by macrophages. Direct evidence that tumor-induced suppression of antitumor resist-
ROBERT J. NORTH, DAVID P. KIRSTEIN, AND RICHARD L. TUTTLE
583
ance, like suppression of antibacterial resistance, is caused by a factor in
circulation will appear in a forthcoming publication.
In spite of the acquisition of a mechanism of macrophage-mediated resistance
to a tumor cell challenge, the host remained unable to reject its primary tumor.
It is highly significant in this connection that the factor which interferes with
macrophage function continues to be produced and liberated into the circulation
during growth of the primary tumor. This implies that its most likely source is
the tumor. If so, it may be present in a large enough concentration in the tumor
bed to protect the primary tumor from macrophage-mediated antitumor immunity. It is well to realize that the demonstration of concomitant resistance is an
artificial procedure in t h a t the introduction of tumor cells with a needle is in
itself sufficient to cause a local inflammatory response. It is considered possible
that this would result in an influx of enough circulating activated mononuclearphagocytes into a nonvascularized deposit of loose tumor cells to cause tumor
cell destruction. The conditions in the vascularized bed of a large established
tumor, obviously, are quite different from those that exist at the site of a tumor
cell challenge.
An additional artificiality in this study was the initiation of growth of transplantable tumors by subcutaneous injection of 10~-10~ cells. This bears little
resemblance to the way in which autochthonous malignancies naturally
emerge. It is therefore right to question the significance to tumor biology of the
rapid creation of the short-term state of severely suppressed antitumor and
antibacterial resistance t h a t resulted from injection of this comparatively enormous number of tumor cells. It can be stated in defense of the model, however,
that it has been shown in this laboratory (unpublished observations) that a
similar degree of suppression occurs after injection of as few as 103 tumor cells,
but not until after a delay of 2 days. In this case, moreover, antibacterial
resistance remains suppressed for a much longer period of time, a period that
corresponds to the period of '~latency" before tumor growth becomes manifest.
The employment of small numbers of tumor cells for studying the mechanism
that enables a small incipient tumor mass to avoid destruction by the host's
defenses over a long period of time will be the subject of a paper now in
preparation.
Summary
Subcutaneous injection of murine tumor cells first resulted in a state of
severely suppressed macrophage-mediated antibacterial resistance and then in
a contrasting state of greatly enhanced antibacterial resistance. Whereas, the
state of suppressed antibacterial resistance corresponded to a state of suppressed
resistance to a tumor cell challenge, the generation of enhanced antibacterial
resistance corresponded to the acquisition of concomitant antitumor immunity.
It was suggested on the basis of this evidence that changes in the level of
macrophage-mediated antibacterial resistance that occur during growth of the
primary tumor reflected changes in the level of the host's resistance to the tumor
itself. It was further suggested that the coincidental suppression of antibacterial
and antitumor resistance that occurs during the initial stages of growth of the
primary tumor represents the operation of a mechanism that enables the tumor
584
SUBVERSION OF HOST DEFENSE M E C H A N I S M S . II
to avoid destruction by m a c r o p h a g e s . The r e s u l t s s u p p o r t the view t h a t macrop h a g e s p l a y a n i m p o r t a n t role in n a t i v e a n d acquired r e s i s t a n c e to m a l i g n a n t
tumors.
Received for publication 26 November 1975.
References
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mechanisms by murine tumors. I. A circulating factor that suppresses macrophagemediated resistance to infection. J. Exp. Med. 143:000.
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3. Robinette, E. H. and D. N. Mardon. 1975. Delayed lethal response to Candida
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6. Keller, R. 1974. Mechanisms by which activated normal macrophages destroy syngeneic rat tumor cells in vitro: cytokinetics, noninvolvement of T lymphocytes, and
effect of metabolic inhibitors. Immunology. 27:285.
7. Hibbs, J. B., L. H. Lambert, and J. S. Remington. 1972. In vitro non-immunological
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macrophages. Proc. Soc. Exp. Biol. Med. 139:1049.
8. Germain, R. N., R. M. Williams, and B. Benacerraf. 1973. Specific and nonspecific
antitumor immunity. II. Macrophage-mediated nonspecific effector activity induced
by BCG and similar agents. J. Natl. Cancer Inst. 54:709.
9. Old, L. J., D. A. Clark, B. Benacerraf, and M. Goldsmith. 1960. The reticuloendothelial system and the neoplastic process. Ann. N. Y. Acad. Sci. 88:264.
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cancer. Br. J. Surg. 57:748.
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