Psychon euroimmunology

Implications for Oncology?

Dana H. Bovbjerg, PHD
Accumulating evidence indicates that the central nervous system (CNS) may
regulate the activity of the immune system. Although the overall significance of
the immune system in cancer remains controversial, psychosocial influences on
immune function could potentially provide a mechanism to account for some
of the reports of an association between psychosocial factors and cancer prognosis.
Cancer 67:828-832.1991.

has witnessed an explosion of interest in the possibility that the central nervous system (CNS) and the immune system communicate with
each other. Increasingly sophisticated interdisciplinary
research has documented effects of psychologic and neural
processes on the activities of the immune system and,
conversely. effects of immune processes on the CNS.-
This article provides a brief overview of this accumulating
evidence and highlights the potential implications for
cancer, particularly the provocative possibility that psychoneuroimmune interactions could be one of the biologic
mechanisms underlying correlations between psychologic
factors and cancer.
Potential channels of communication that the CNS
could use to regulate the activities of the immune system
include autonomic innervation of lymphoid organs and
classical neuroendocrine responses.6 Leukocytes have
been shown to bear functional receptors for a wide variety
of neurotransmitters, neuropeptides, and hormones.6
Studies of sympathetic innervation of lymphoid organs
have progressed to the point where some investigators7
have concluded that norepinephrine fulfills the classic criteria for neurotransmission established in more conventional target tissues, such as the heart. Endocrine influences on the immune system include the well-known potent effects of glucocorticoids, although their physiologic
HE PAST DECADE

Presented at the American Cancer Societys Second Workshop on

Methodology in Behavioral and Psychosocial Cancer Research, Santa
Monica, California, December 5-8, 1989.
From the Department of Neurology, Memorial Sloan-KetteringCancer
Center, New York, New York.
Supported in part by a Junior Faculty Research Award from the
American Cancer Society.
Address for reprints: Dana Bovbjerg, PhD. Psychoneuroimmunology
Laboratory, Box 457, Memorial Sloan-Kettering Cancer Center. 1275
York Avenue, New York. NY 10021.
Accepted for publication August 13, 1990.

role remains controversial. Many other hormones and

neuropeptides (e.g., endogenous opiates) have also been
found to modulate immune
Evidence for afferent pathways between the immune
system and the CNS has come primarily from animal
experiments. Stimulation of the immune system by injection of antigen has been reported to alter neuronal firing
rates and neurotransmitter levels in localized regions of
the brain.6 A possible mechanism for such effects is suggested by studies showing that factors secreted by leukocytes (cytokines) can influence both immune and CNS
processes. Interleukin- 1 (IL-l), for example, induces a
constellation of effects including increased lymphocyte
proliferation, increased body temperature, and increased
adrenocorticotrophic hormone (ACTH) levek6 Leukocytes have also been reported to produce at least a dozen
peptide hormones (including ACTH and enkephalins)
long thought to be restricted to the neuroendocrine system. This commonality of messenger molecules between
the CNS and immune system has led to speculation that
one function of the immune system may be to serve as a
sensory organ, informing the CNS of noncognitive
stimuli, such as the presence of bacteria or viruses. The
evidence for physiologic pathways linking the CNS and
the immune system suggests that hardwiring is in place
for regulation of the immune system by the CNS. If such
regulation occurs, one would expect to find more direct
evidence of regulatory processes (software). Houk has
argued that regulation of physiologic systems is accomplished by three basic automatic control strategies: feedback, feedfonvard, and adaptive control. Feedback control
(e.g., a thermostat) involves the monitoring of the effects
of environmental challenge (a blizzard) on the regulated
variable (room temperature) and a directed response
(heat), which lasts until the variable is back in an appropriate range.12 An example of feedback regulation in-

828

No. 3

PSYCHONEUROIMMUNOLOGY Bovbjerg

volving the CNS and the immune system comes from

Besedovsky6and others who have noted that stimulation
of monocytes induces the secretion of IL- 1, which results
in increased levels of ACTH, which in turn increases corticosteroid levels, which in turn reduces the production
of IL- 1. Feedforward control involves the monitoring of
environmental stimuli to predict future challenge to a
regulated variable and direct appropriate anticipatory responses.I2 Examples of feedforward regulation of the immune system have come from studies of classical
conditioning. Both conditioned enhancement and conditioned suppression of a variety of immune responses
have been reported in animal e~perirnents.~.~
This initial evidence for feedback and feedforward
control of the immune system is consistent with the idea
that the CNS regulates the activities of the immune system.
The extent of that regulation has yet to be determined.
The CNS could be capable of fine tuning immune
functions (e.g.. down-regulating responses to a specific
antigen), or its capabilities could be limited to general
influences (e.g., down-regulating all responses). The CNS
could also interact with cells involved in the regulatory
circuits within the immune system (e.g.. helper cells)
and thus have subtle but powerful influences on immune
function.
The evidence that the CNS regulates the activities of
the immune system raises the possibility that psychologic
factors could have an impact on the control processes and
thus affect immune function. The relationship between
psychosocial variables and immune function has received
increasing research attention in recent years.15 Investigators have reported associations between altered immune
function and psychologic factors of both long (e.g.,
depression) and short (e.g., anxiety)
The most extensively replicated finding in this literature
is the association between times of psychologic distress
and reductions in proliferative response of lymphocytes
cultured with mitogens, particularly mitogens that activate
T-cells.I8This in vitro measure of lymphocyte activation,
although apparently sensitive to psychosocial influences,
has yet to be definitively linked to any disease outcome.
More apposite to issues of immune responses and cancer
are studies that have explored the relationships between
psychosocial variables and natural killer (NK) cell activity.
Studies of three different populations (medical students,
geriatric residents of independent-living facilities, and
nonpsychotic psychiatric inpatients) have supported an
association between psychosocial factors and NK cell activity. For example, NK cell activity was lower in lymphocytes isolated from blood samples collected during
medical students examinations than during nonexamination periods. In addition, students with greater self-reported levels of loneliness had lower levels of NK cell

829

activity during both periods. Concurrent assessment of

several behavioral variables that might alter immune
measures (e.g.. amount of sleep) did not support the possibility that changes in such behaviors were responsible
for the reduced NK cell activity. Further support for a
more direct relationship between psychosocial variables
and altered immune measures was provided by an intervention, relaxation training, which resulted in decreased
distress and increased NK cell activity in geriatric resid e n t ~ .These
~ studies and others support the link between
psychosocial factors and alterations in immune function.
As yet unknown are the relative contribution of psychologic influences compared with more automatic CNS influences or influences within the immune system itself.
The inherent methodologic difficulties in this area of
research and occasional methodologic shortcomings of
published reports suggest that findings should be viewed
with cautious optimism.
The accumulating evidence that psychosocial factors
can alter immune function has been largely responsible
for engendering interest in the potential relevance of psychoneuroimmunology for cancer research. Psychosocial
influences on immune function have been viewed as providing a biologic mechanism that could potentially account for previous reports of an association between psychosocial factors and cancer.20,2This view is based on
three independent areas of research that have addressed
the following hypotheses: (1) some cancers are influenced
by psychosocial processes, (2) some cancers are influenced
by the activities of the immune system, and ( 3 ) some activities of the immune system are influenced by psychosocial factors.22
The extensive literature exploring the involvement of
psychosocial factors in cancer etiology, progression, or
response to treatment has been reviewed el~ewhere.~,~~~
Retrospective studies, comparing patients with cancer to
nonpatient subjects, have been most common. Although
such retrospective studies are widely recognized to be
flawed by the effects of patients knowledge of their prognosis, they have revealed three general categories of psychosocial variables that appear to be related to cancer: a
history of psychologic distress, social support, and personality.2 Because researchers have often used idiosyncratic personality measures and because negative findings
usually go unreported, it is difficult to the determine the
replicability of the correlations that have been rep~rted.~
The sheer number of personality variables claimed to be
associated with cancer reflects a weakness of the field because of the difficulty of comparing results from studies
using different measures.
Prospective studies, although relatively rare, have provided support for a relationship between some psychosocial factors and the incidence or progression of a number

830

CANCERFebruary I Supplement 199 1

of neoplastic diseases, but contradictory findings remain.21

Many of the effects of psychosocial factors are likely to
be mediated by behavioral choices (e.g., smoking) that
are known to affect the risk of cancer. The determination
of causal links between psychosocial factors and the incidence of cancer is also obscured by the long delay between the initiation of malignancy and the detection of
neoplastic disease.24One recent prospective study of patients with metastatic breast cancer has documented a
significant effect of a psychosocial intervention on survival.6 The random assignment of patients to intervention
and control groups in this intriguing study reduces the
likelihood of alternative explanations for the results. The
authors were careful to point out, however, that the intervention may have resulted in increased compliance
with medical treatment and thus had an indirect effect
on disease.
Variables that confound studies of psychosocial influences on cancer in humans could, in principle, largely be
eliminated in studies with research animals. For example,
putative psychosocial influences on the incidence or
progression of various types of tumors could be explored
by use of well-characterized carcinogens; animals with
known genetic susceptibility for tumors; or transplantable
tumor cell lines, which can be injected in known quantities
at specified times. Unfortunately such animal research
has yet to fulfill its promise. Conflicting findings are comwhich could be due to differences in the choice
of experimental tumor, or the timing, or type of psychosocial manipulation (q.,
a wide variety of stressors
have been used). Even differences in the animal housing
facilities could have an impact.28In addition to the choice
of psychosocial variable, the choice of experimental tumor
is important when considering the relevance of animal
studies to humans. Many of the animal tumors used for
research are highly immunogenic, provoking strong immune responses, whereas strong immune responses to tumors are the exception in humans.30 Many spontaneous
rodent tumors are viral (and may thus express viral antigens that can be recognized by specific immune defenses), whereas relatively few human tumors are currently
thought to have a viral etiology.25It should also be noted
that many animal studies involve transplantation of relatively large numbers of tumor cells previously induced
(by viral or chemical means) in other genetically identical
hosts; the results of such studies may provide information
relevant to understanding mechanisms related to the progression of cancer in humans but are unlikely to have
applicability to early stages in the development of neoplastic disease.
The evidence for the involvement of the immune system in defending against cancer remains controversial.
Tumors can be induced by a number of different mech-

Vol. 61

anisms, including DNA tumor viruses, retrovirus insertion

near a cellular oncogene, and cellular oncogene activation
occumng spontaneously or as a result of carcinogen exp ~ s u r e .One
~ possible role for the immune system would
be to recognize cells in which such changes have occurred
and to eliminate them before a tumor can develop, as
hypothesized by immune surveillance theories.32 Additional immune defenses might come into play to block
the subsequent growth or metastasis of tumors that escaped s ~ r v e i l l a n c eThe
. ~ ~ capabilities of the immune system to perform any of these three tasks remain controversial despite thousands of research report^.^^,^^ Moreover, there is evidence that the immune system can
enhance the growth of some tumors as well as inhibit it.36
Specific adaptive immune responses (e.g., by cytotoxic
T-cells) to malignant cells presuppose the expression of
cell surface markers (antigens) unique to the transformed
state. Tumors induced by oncogenic DNA viruses might
be expected to bear viral proteins that could be recognized
as foreign by lymphocytes and thus specifically targeted
for d e s t r u ~ t i o n Such
. ~ ~ immune defenses against tumorspecific transplantation antigens are well known in anim a l ~ ,but
~ the existence of analogous antigens on human
tumors remains controversia~.~~
Immunologic recognition
of human neoplasms is more commonly due to quantitative rather than qualitative differences in antigens between tumor and normal cells. Such tumor-associated
antigens have been reported to elicit immune responses
in humans, but the relationship of such responses to prognosis is not well e~tablished.~
The limited effectiveness
of specific immune responses could in part be due to suppressor mechanisms within the immune system (suppressor cells) or from the t ~ m o r . ~ ~ , ~
Perhaps the most provocative evidence of the potential
impact of specific antitumor responses comes from recent
preliminary reports that immunotherapy using monoclonal antibodies or cytotoxic T-cells can be an effective
treatment for some types of ~ a n c e r . ~ For
, ~ *example, preliminary results of a clinical trial43indicated that nine of
15 patients with metastatic melanoma who were infused
with tumor-infiltrating lymphocytes and interleukin-2 (IL2) showed objective regression of their cancer. Based on
previous experiments with animal^,"^ these patients were
pretreated with an immunosuppressive drug (cyclophosphamide) to reduce the numbers of suppressor cells that
could potentially block the antitumor response.
In addition to specific adaptive immune responses to
tumors, considerable evidence suggests a role for nonspecific natural immunity, involving NK cells, K-cells, granulocytes, and macrophages. Activated macrophages have
been reported to kill a variety of phenotypically distinct
tumor cells.45A considerable literature indicates that NK
cells can kill tumor cells of many different types (although

No. 3

PSYCHONEUROIMMUNOLOGY
Bovbjerg

not all) when tested either in culture or in animals.46

Studies in both animals and humans have suggested that
NK cells are particularly important in the elimination of
metastatic tumor cells.46As with specific responses, NK
cell activity can be suppressed or enhanced by factors (e.g.,
interferon) produced by other cells in the immune
system.35
In light of the independent evidence for a relationship
between psychosocial factors and cancer, the evidence that
the immune system plays a role in cancer raises the possibility that psychoimmune interactions may play a role
in cancer. Few investigators have concurrently explored
the influence of psychologic and immune variables on
cancer outcome. One noteworthy exception comes from
animal studies by Shavit el
who reported that a particular pattern of electrical foot shock (known to induce
the release of endogenous opiates) reduced NK cell activity
and reduced the survival time of rats implanted with a
mammary adenocarcinoma. The reduction in survival
time was blocked by treatment with the opiate antagonist
naltrexone and was mimicked by treatment with mor~ h i n e . ~However,
'
rats receiving a different pattern of foot
shock (nonopioid but of identical intensity and total duration) did not exhibit altered NK cell activity or changes
in survival time.
Research examining psychosocial and immune variables within a single group of cancer patients for exploration of possible relationships to prognosis is scant. Levy
et a1.49,50
have reported that half of the variance in NK
cell activity in breast cancer patients a week after surgery
could be accounted for by three measures of psychologic
distress. Differences in NK cell activity were, in turn, related to a prognostic variable, the number of positive
lymph nodes. These findings, although controver~ial,~'
are consistent with the possibility that psychoimmune relations may indeed play a role in prognosis. The potential
impact of psychosocial variables on immune measures
also suggests a caution for studies attempting to document
immunologic abnormalities associated with cancer. Failure to consider the concurrent influence of psychologic
variables on immune function in patients who face the
major life stresses of disease and treatment could obscure
significant relationships between neoplasia and underlying
immune variables.
In conclusion, this brief review of the research related
to possible psychoneuroimmunologic processes in cancer
provides support for the following three hypotheses: (1)
the outcome of some cancers can be influenced by psychosocial factors; (2) the activities of the immune system
can influence the outcome of some cancers; and (3) at
least one immune response (NK cell activity), thought to
play a role in defenses against cancer, appears to be influenced by psychosocial factors. Alterations in immune de-

83 1

fenses should be investigated as a possible mechanism by

which psychosocial factors could influence cancer. In addition, future research should explore the possible relevance of psychoimmune relationships to the continuing
clinical problem of infection in cancer patient^.^'
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