DOI 10 1093 annonc mdf655 Psycho oncology and cancer psychoneuroimmunology and cancer J K Kiecolt Glaser1 2 5 T F Robles3 K L Heffner1 T J Loving1 R Glaser2 4 5 1 Department of Psychiatry 2The Ohio State University Comprehensive Cancer Center 3Department of Psychology 4Department of Molecular Virology Immunology and Medical Genetics 5The Institute for Behavioral Medicine Research The Ohio State University Medical Center Columbus Ohio USA Introduction Stress and immune dysregulation A growing body of research linking psychological and behavioral factors to the incidence and progression of cancer suggests that psychosocial factors may have an impact on some types of cancer 1 6 In this paper we suggest that it is through the impact these behavioral and psychological factors have on the cellular immune response including natural killer NK cell function that they may ultimately affect the occurrence and progression of certain tumors Our discussion of this link begins with a brief overview of the evidence that psychoneuroimmunology PNI research with healthy individuals may be relevant to cancer Next to link extant PNI research findings with tumorigenesis we draw upon two important PNI findings relating psychological distress to two important aspects of carcinogenesis i poorer repair of damaged cellular DNA and ii modulation of apoptosis Finally we focus on the implications of intervention research in cancer patients for cancer progression and treatment Before reviewing the evidence regarding stress related immunological changes it should be noted that one recurrent concern in the literature is the question of the significance of the immune system for cancer Cancer is comprised of a heterogeneous group of diseases with multiple etiologies 1 and immunological involvement varies across different cancers Those cancers that are induced by chemical carcinogens e g lung cancer may be less influenced by psychological behavioral and immunological factors than cancers that are associated with a virus such as Epstein Barr Virus EBV which are immunogenic Suppression of cellular immunity is associated with a higher incidence of certain types of tumors particularly EBV associated lymphoproliferative diseases in organ transplant patients and Kaposi s sarcoma and EBVassociated B cell lymphoma in AIDS patients 7 Additionally some researchers have questioned whether stress related immune changes are of either the type or the magnitude to influence tumor growth and metastases 3 8 While such issues are beyond the scope of this paper compelling evidence exists for the role of cells such as NK cells in resisting the progression and metastatic spread of tumors once they have developed 7 Across a broad number of studies stressors are associated with dysregulation of the immune system In particular decreased lymphocyte proliferation and reduced NK cell cytotoxicity are consistently observed in the literature 9 As noted above our discussion of stress related immune changes highlights NK cells because of their importance for cancer 10 NK cells play an important role in a variety of immune functions including defense against viral infections 11 and surveillance of tumor cells 12 NK cell cytotoxicity can be downregulated by stress presumably through neuroendocrine mechanisms 5 13 14 Cytokines such as interferon IFN and interleukin 2 IL 2 can enhance NK cell and lymphocyte activated killer LAK cell cytotoxicity 12 There is evidence that stress can modulate IFN and IL 2 synthesis by mitogen treated peripheral blood leukocytes PBLs 15 16 Interferon is a major regulator of NK cells stimulating their growth and differentiation as well as enhancing their ability to destroy target cells 7 Among 40 second year medical students the production of IFN by lymphocytes stimulated with concanavalin A Con A plummeted from a mean of 2000 ml at baseline to 80 ml during final exams 13 a finding subsequently replicated across several exam series 15 Studies using individuals who were caregiving for a spouse with Alzheimer s disease provided data on the immunological consequences of chronic stress in older individuals One series of studies focused on NK cells We examined differences in NK cell activity among current dementia spousal caregivers former bereaved caregivers whose spouse had died and noncaregiving controls Consistent with other work 17 we found no differences in NK cell cytotoxicity in PBLs obtained from continuing or former caregiver groups or control subjects However PBLs from both continuing and former caregivers had a significantly poorer NK cell response to recombinant interferon rIFN or recombinant interleukin 2 rIL 2 in vitro 18 Moreover caregivers who were low NK cell responders to both cytokines reported significantly less positive social support less emotional closeness in their social contacts and more physician visits for infectious illness symptoms compared with caregivers who were high 2002 European Society for Medical Oncology 166 responders to at least one of the two cytokines A follow up study using effector cell preparations enriched for NK cells approximately 90 replicated the previously observed group differences between caregivers current and former and controls 19 Several subsequent studies have also suggested a link between personal relationships and NK cell cytotoxicity consistent with the wide range of literature on social support and health 20 For example bereaved spouses had elevated cortisol and decreased NK cell activity 21 Among spouses of cancer patients those who reported lower levels of social support had lower levels of NK cell cytotoxicity 22 In a study of newlywed couples those who were more negative or hostile during a discussion of marital problems with the spouse showed greater downward change in NK cell activity 24 h later 23 Evidence using rodent models shows that social stressors not only decrease NK cell cytotoxicity they also enhance metastasis of transplantable tumors 24 25 Collectively these studies demonstrate that stress can dysregulate NK cell function including depressing the stimulatory response of NK cells to cytokines Psychosocial factors may also act in concert with other risk factors for cancer to promote immune dysregulation For instance depression and smoking had synergistic effects on reduced NK cell lysis 26 It should be noted that there is good evidence that several aspects of the cellular immune response are also adversely affected by psychosocial stress 9 27 It