DOI: 10.1093/annonc/mdf655© 2002 European Society for Medical OncologyPsycho-oncology and cancer: psychoneuroimmunology and cancerJ. K. Kiecolt-Glaser1,2,5, T. F. Robles3, K. L. Heffner1, T. J. Loving1 & R. Glaser2,4,51Department 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, USAIntroductionA growing body of research linking psychological andbehavioral factors to the incidence and progression of cancersuggests that psychosocial factors may have an impact onsome types of cancer [1–6]. In this paper, we suggest that itis through the impact these behavioral and psychologicalfactors have on the cellular immune response, includingnatural killer (NK) cell function, that they may ultimatelyaffect the occurrence and progression of certain tumors. Ourdiscussion of this link begins with a brief overview of theevidence that psychoneuroimmunology (PNI) research withhealthy individuals may be relevant to cancer. Next, to linkextant PNI research findings with tumorigenesis, we drawupon two important PNI findings relating psychologicaldistress to two important aspects of carcinogenesis: (i) poorerrepair of damaged cellular DNA and (ii) modulation of apop-tosis. Finally, we focus on the implications of interventionresearch in cancer patients for cancer progression and treat-ment.Before reviewing the evidence regarding stress-relatedimmunological changes, it should be noted that one recurrentconcern in the literature is the question of the significance ofthe immune system for cancer. Cancer is comprised of a hetero-geneous group of diseases with multiple etiologies [1], andimmunological 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 areassociated with a virus, such as Epstein–Barr Virus (EBV),which are immunogenic. Suppression of cellular immunity isassociated with a higher incidence of certain types of tumors,particularly EBV-associated lymphoproliferative diseases inorgan transplant patients, and Kaposi’s sarcoma and EBV-associated B-cell lymphoma in AIDS patients [7]. Addition-ally, some researchers have questioned whether stress-relatedimmune changes are of either the type or the magnitude toinfluence tumor growth and metastases [3, 8]. While suchissues are beyond the scope of this paper, compelling evidenceexists for the role of cells, such as NK cells, in resisting theprogression and metastatic spread of tumors once they havedeveloped [7].Stress and immune dysregulationAcross a broad number of studies, stressors are associated withdysregulation of the immune system. In particular, decreasedlymphocyte proliferation and reduced NK cell cytotoxicity areconsistently observed in the literature [9]. As noted above, ourdiscussion of stress-related immune changes highlights NKcells because of their importance for cancer [10]. NK cellsplay an important role in a variety of immune functions,including defense against viral infections [11] and surveil-lance of tumor cells [12]. NK cell cytotoxicity can be down-regulated by stress, presumably through neuroendocrinemechanisms [5, 13, 14].Cytokines such as interferon-γ (IFN-γ) and interleukin-2(IL-2) can enhance NK cell and lymphocyte-activated killer(LAK) cell cytotoxicity [12]. There is evidence that stress canmodulate IFN-γ and IL-2 synthesis by mitogen treated peri-pheral blood leukocytes (PBLs) [15, 16]. Interferon is a majorregulator of NK cells, stimulating their growth and differenti-ation, as well as enhancing their ability to destroy target cells[7]. Among 40 second-year medical students, the productionof IFN-γ by lymphocytes stimulated with concanavalin A(Con A) plummeted from a mean of 2000 µ/ml at baselineto 80 µ/ml during final exams [13], a finding subsequentlyreplicated across several exam series [15].Studies using individuals who were caregiving for a spousewith Alzheimer’s disease provided data on the immunologicalconsequences of chronic stress in older individuals. One seriesof studies focused on NK cells. We examined differences inNK cell activity among current dementia spousal caregivers,former (bereaved) caregivers whose spouse had died, andnoncaregiving controls. Consistent with other work [17], wefound no differences in NK cell cytotoxicity in PBLs obtainedfrom continuing or former caregiver groups or control sub-jects. However, PBLs from both continuing and former care-givers had a significantly poorer NK cell response torecombinant interferon-γ (rIFN-γ) or recombinant interleukin2 (rIL-2) in vitro [18]. Moreover, caregivers who were lowNK cell responders to both cytokines reported significantlyless positive social support, less emotional closeness intheir social contacts and more physician visits for infectiousillness symptoms compared with caregivers who were high166responders to at least one of the two cytokines. A follow-upstudy using effector cell preparations enriched for NK cells(approximately 90%) replicated the previously observedgroup differences between caregivers (current and former)and controls [19].Several subsequent studies have also suggested a linkbetween personal relationships and NK cell cytotoxicity,consistent with the wide range of literature on social supportand health [20]. For example, bereaved spouses had elevatedcortisol and decreased NK cell activity [21]. Among spousesof cancer patients, those who reported lower levels of socialsupport had lower levels of NK cell cytotoxicity [22]. In astudy of newlywed couples, those who were more negative orhostile during a discussion of marital problems with thespouse showed greater downward change in NK cell activity24 h later [23]. Evidence using rodent models shows thatsocial stressors not only decrease NK cell cytotoxicity, theyalso enhance metastasis of transplantable tumors [24, 25].Collectively, these studies demonstrate that stress can dys-regulate NK cell function, including depressing the stimulat-ory response of NK cells to cytokines. Psychosocial factorsmay also act in concert with other risk factors for cancer topromote immune dysregulation. For instance, depression andsmoking had synergistic effects on reduced NK cell lysis [26].It should be noted