Psychologic Stress, Immunity, and Cancer

(Editorial from the Journal of the National Cancer Institute, January 7, 1998))

Sheldon Cohen, Bruce S. Rabin*

Why publish an article in a major cancer journal that demonstrates an association between psychologic stress and cellular
immune function in cancer patients? The potential interest in articles such as Andersen et al. (1), published in this issue of the
Journal, is based on the premise that stress may alter the function of the immune system in a manner that influences the
development or growth of malignant tissue. This premise is quite controversial and we use this editorial to discuss its underlying
assumptions.

1) Psychologic stress can alter immune function.

There is evidence for a number of mechanisms through which psychologic stress might alter immune function (2). These include
direct innervation of lymphatic tissue by the central nervous system and stress-elicited release of hormones from the brain that
bind to and alter the functions of immunologically active cells. The mechanisms also include behavioral changes that often occur
in response to stress: an increase in smoking, an increase in drinking alcohol, a loss of sleep, a reduction in exercise, a
degradation of the diet, and a decrease in adherence to medical regimens.

In fact, healthy humans exposed to stressful tasks that last only a few minutes, including difficult cognitive tasks and tasks that
induce social anxiety, show suppression of T-cell mitogenesis, and increased numbers of circulating CD8 and natural killer cells
(3). Studies of real-life stressors show similar alterations. Living near the Three Mile Island nuclear power plant at the time of
the accident, caretaking for a relative with Alzheimer's disease, taking medical school examinations, and clinical depression
have all been associated with alterations in both the numbers and functions of various subpopulations of lymphocytes (4).
These alterations include a reduced proliferative response to mitogen stimulation, reduced natural killer cell cytotoxicity, as well
as changes in the production of cytokines. Although the range of stress' effects on immune function is wide, the magnitude of
the effects is small, with stress-suppressed patients usually functioning within the normal range.

2) The immune system plays a role in regulating tumor growth.

Burnet (5) promoted the ``immune surveillance'' theory which postulated that the immune system was capable of eliminating
neoplastic cells that developed in the normal individuals. It is likely that the mechanisms of cellular immunity are important to the
functioning of immune surveillance. Indeed, subjects who undergo suppression of immune function by pharmacologic means, or
who have immunodeficiency diseases, have an increased risk of cancer. This has led to the experimental use of treatment
strategies designed to increase the function of the immune system and to focus immune reactants at the site of malignant tissue.
The use of immune-enhancing therapies, primarily in patients with malignant melanoma and renal cell carcinoma, has produced
limited antitumor responses (6).

3) Immune changes under stress are of the type that would influence tumor growth and metastasis.

There are a variety of stress-induced changes in lymphocyte surface molecules, the potential for cell division, and cytokine
production that may play a role in immune regulation of cancer growth. Although there is no direct evidence associating these
changes in immunity with disease progression in patients with cancer, animal models suggest that the antitumor cytotoxicity of
CD8 and NK lymphocytes and the localized inflammatory response mediated by CD4 lymphocytes may influence tumor
growth and metastasis (7). These data are suggestive, but specific immune mechanisms that may suppress cancer in humans
are not yet known. Therefore, it is speculative at best to assume that psychologic stress modifies immune components involved
in the regulation of tumor growth in cancer patients.

4) Immune changes under stress are of the magnitude that would influence tumor growth and metastasis.

The evidence for an association between suppressed immune function and the onset of cancer derives from cases of profound
immunosuppression. These cases include tissue transplant recipients receiving immunosuppressive drugs and individuals with
immunodeficiency diseases. However, the associations between stress and immune system function is quite mild in other
individuals, with immune function still remaining within normal parameters (4). Such changes seem unlikely to have a clinically
significant effect on tumor growth. Even so, stress has been found to be an important predictor of other diseases that occur
when there is a failure in immune regulation, including greater susceptibility to and severity of respiratory infections and the
onset and severity of autoimmune diseases (4). That stress is a risk factor for these diseases raises the possibility that even
small stress-induced changes in immune function might be important clinically. It also suggests that, even if stress does not
influence the course of cancer, it might alter the risk of infection and for other immune-related diseases, especially among
patients receiving chemotherapy.

5) Stress-reduction interventions will influence the progression of disease.

There is evidence that the reduction of stress by the provision of social support may be associated with an amelioration in the
course of some malignant diseases. For example, a study of women with metastatic breast cancer showed an 18-month
increase in survival (8), and a study of men and women with melanoma showed increased survival and reduced recurrence
after 5-6 years (9). Although the latter study found that the intervention was also effective in increasing natural killer cell
cytotoxicity, no associations were observed between this change in immune function and disease recurrence or mortality.

It can be argued that attempts to increase immune function by stress reduction strategies may have only limited effects on
immunity and consequently on disease progression. Moreover, the effectiveness of these interventions may be further reduced
by the influence of chemotherapeutic agents on immune function. Nevertheless, the provocative findings that social support
interventions reduce mortality are hard to ignore. However, it is not clear that the effects of these interventions on mortality are
mediated through immune mechanisms. It is possible that the interventions might work through other pathways, such as by
increasing adherence to medication or nutritional regimens or by ameliorating the direct effects of stress-induced endocrine
response on tumor growth.

In sum, Andersen et al. (1) have linked psychologic experience to immunity in patients whose immune systems are already
compromised by disease. The question remains whether the immune changes associated with stress have implications for
cancer progression and metastasis. If they do, it also remains to be seen whether stress-reduction interventions can ameliorate
cancer progression through immune enhancement. The article by Andersen et al. provides an important piece of this fascinating
puzzle, but the solution is still a ways off.

References

(1) Andersen BL, Farrar WB, Golden-Kreutz D, Kutz LA, MacCallum R, Courtney ME, et al. Stress and immune responses
after surgical treatment for regional breast cancer.J Natl Cancer Inst 1998; 90: 30-6. Medline Abstract

(2) Rabin BS, Cohen S, Ganguli R, Lysle DT, Cunnick JE. Bidirectional interaction between the central nervous system and
immune system.Crit Rev Immunol 1989; 9: 279-312. Medline Abstract

(3) Kiecolt-Glaser JK, Cacioppo JT, Malarkey WB, Glaser R. Acute psychologic stressors and short-term immune changes:
what, why, for whom, and to what extent? [editorial].Psychosom Med 1992; 54: 680-5. Medline Abstract

(4) Cohen S, Herbert TB. Health psychology: psychologic factors and physical disease from the perspective of human
psychoneuroimmunology.Annu Rev Psychol 1996; 47: 113-42. Medline Abstract

(5) Burnet FM. Immunological surveillance in neoplasia.Transplant Rev 1971; 7: 3-25. Medline Abstract

(6) Rosenberg SA. Karnofsky Memorial Lecture: the immunotherapy and gene therapy of cancer.J Clin Oncol 1992; 10:
180-99. Medline Abstract

(7) Lynch SA, Houghton AN. Cancer immunology.Curr Opin Oncol 1993; 5: 145-50. Medline Abstract

(8) Spiegel D, Bloom JR, Kraemer HC, Gottheil E. Effect of psychosocial treatment on survival of patients with metastatic
breast cancer.Lancet 1989; 2: 888-91. Medline Abstract

(9) Fawzy FI, Fawzy NW, Hyun CS, Elashoff R, Guthrie D, Fahey JL, et al. Malignant melanoma. Effects of an early
structured psychiatric intervention, coping, and affective state on recurrence and survival 6 year later.Arch Gen Psychiatry
1993; 50: 681-9. Medline Abstract


*Affiliations of authors: S. Cohen, Department of Psychology, Carnegie Mellon University, Pittsburgh, PA; B. S. Rabin,
Department of Pathology, University of Pittsburgh School of Medicine.

Correspondence to: Sheldon Cohen, Ph.D., Department of Psychology, Carnegie Mellon University, Pittsburgh, PA 15213.



Copyright© Oxford University Press, 1998.