Natural killer (NK) activity in peripheral blood lymphocytes of patients with benign and malignant breast disease

Physiological responses that involve adrenergic mechanisms, such as stress-induced changes in cardiovascular indices, were reported to fluctuate along the menstrual cycle. Metastatic development following surgery was also reported to vary according to the menstrual phase during which a primary breast tumour was removed. Natural killer (NK) cells are believed to play an important role in controlling metastases. Our recent studies in rats demonstrated that adrenergic suppression of NK activity and of resistance to metastasis is more profound during oestrous phases characterized by high levels of oestradiol. In the current study in humans, we examined the in vitro impact of a β-adrenergic agonist, metaproterenol (MP), on NK activity, comparing blood drawn from (a) women tested at 3–4 different phases of their menstrual cycle ( n = 10), (b) women using oral contraceptives (OC) ( n = 10), and (c) men ( n = 7). NK activity in each blood sample was assessed in the presence of 5 different concentrations of MP (10 –8 M to 10 –6 M), and in its absence (baseline). The results indicated marked group differences in the magnitude of NK suppression by MP: EC 50 was 2.6-fold lower in the luteal phase compared to the follicular phase, and 1.8-fold lower in OC users compared to men, who were least susceptible to the effects of MP. No significant group differences or menstrual effects in baseline levels of NK activity were evident. These findings provide the first empirical evidence for menstrual regulation of adrenergic impact on cellular immune competence. Relevance of these findings to the relation between the timing of breast cancer excision within the menstrual cycle and survival rates is discussed. © 2000 Cancer Research Campaign http://www.bjcancer.com

Section: Discussionmentioning

confidence: 55%

“…Some reported a decrease in NK activity during the follicular phase (White et al, 1982), some a significant reduction around the periovulatory period (Sulke et al, 1985), and others reported no differences (Thyss et al, 1984). Animal studies are also inconsistent in this respect (Hrushesky et al, 1988;Ben-Eliyahu et al, 1996).…”

mentioning

confidence: 99%

Timing within the menstrual cycle, sex, and the use of oral contraceptives determine adrenergic suppression of NK cell activity

Shakhar

Rosenne

et al. 2000

“…Thus, it is likely that this phenomenon reflects an indirect effect of sex hormones on tumour development. Immune functions that control neoplasia, such as natural killer cell, macrophage and cytotoxic T cell activities, are potential mechanisms, and human and animal studies demonstrated oestrous/menstrual cycle-related alterations in cellular and humoral immunity (Sulke et al, 1985;White et al, 1982;Gruber et al, 1988;Rager et al, 1994). Sex hormones may directly impact anti-tumour activity of immune effector cells or may alter levels of immune modulators (interleukins, interferons and various hormones).…”

mentioning

confidence: 99%

Increased susceptibility to metastasis during pro-oestrus/oestrus in rats: possible role of oestradiol and natural killer cells

Ben‐Eliyahu

Page²,

Shakhar³

et al. 1996

Summary It has been suggested that tumour development and immunocompetence are affected by the menstrual and the oestrous cycle, and sex hormones have been shown to modulate lymphokine production, neuroendocrine activity and immunity. In this study, we assessed natural killer cell activity and host susceptibility to metastasis during the oestrous cycle in the Fischer 344 inbred rat strain. Females were inoculated intravenously with MADB106 tumour cells, a syngeneic mammary adenocarcinoma cell line that metastasises only to the lungs. The susceptibility to metastatic development of this tumour was found to be significantly higher during pro-oestrus and oestrus than during metoestrus and dioestrus. Two days of exposure to oestradiol benzoate caused similar effects in ovariectomised females, and a single administration of progesterone reduced this effect of oestradiol to a statistically non-significant level. The tumour was found to be negative for oestradiol receptors, and its in vitro proliferation rate was not affected by oestradiol or progesterone, suggesting that the effects of sex hormones on the metastatic process are not attributable to a direct effect on tumour cells. Because the metastatic process of MADB106 tumour cells is known, and confirmed here, to be highly controlled by large granular lymphocyte/natural killer (LGL/NK) cell activity, we assessed their role in mediating the effects of the oestrous cycle. The number and activity levels of circulating blood LG/NK cells (NKR-Pl+bright) were studied. Findings indicated oestrous-dependent alterations in the number of LGL/NK cells and suggested a diminished NK activity per LGL/NK cell during pro-oestrus/ oestrus, the same phases that were characterised by higher susceptibility to metastatic development. These findings provide the first empirical evidence for a causal relationship between a short-term exposure to elevated oestradiol/low progesterone levels and decreased resistance to tumour metastasis, and it is hypothesised that an alteration in LGL/NK cell activity underlies these effects. Homologies and relevance to clinical phenomena are discussed.

“…1976; Vose and Moore. 1980: Uchida and Hoshino, 1980;Cunningham-Rundles et al, 1981;White et al, 1982;Tichatschek et alt, 1988 EBCTCG, 1992) In order to analyse the influence of sera of patients with breast cancer upon lymphocyte proliferation, PBMCs derived from healthy individuals were preincubated with sera diluted 1:10 or 1:100 (v/v), respectively, at 3TC for 3 h and submitted subsequently to PHA assays as above.…”

mentioning

confidence: 99%

Reduced mitogenic stimulation of peripheral blood mononuclear cells as a prognostic parameter for the course of breast cancer: a prospective longitudinal study

Wiltschke

Krainer²,

Budinsky³

et al. 1995

Immunosuppression has been often associated with the course of malignant diseases. In the present study, the proliferation of peripheral blood mononuclear cells (PBMCs) in response to mitogenic stimulation with phytohaemagglutinin (PHA) was assessed prospectively in 90 patients with stage I-III breast cancer. Whereas PHA-induced proliferation of PBMCs derived from patients with breast cancer preoperatively was significantly decreased when compared with data obtained in healthy control individuals (P < 0.001), the degree of the defect in PHA-induced proliferation of PBMCs depended upon the tumour burden as manifested by tumour size and axillary lymph node involvement (P < 0.003 in each case). PHA-induced proliferation of PBMCs dropped significantly in patients who received adjuvant chemotherapy consisting of cyclophosphamide, methotrexate and fluorouracil (CMF) after an observation period of 6 months (P < 0.01), but not in patients under adjuvant treatment with tamoxifen only. After an additional 6 months (i.e. 12 months after surgery), PHA-induced proliferation of PBMCs was similar in patients after adjuvant chemotherapy with CMF and in those receiving continued adjuvant tamoxifen treatment (P > 0.1), but in all patients still significantly decreased as compared with healthy controls (P < 0.001). When data obtained preoperatively and after 12 months were compared, it was found that out of 23 patients whose PBMCs had experienced a drop in their PHA-induced proliferation, 14 (61%) had developed metastatic disease within the subsequent 24 months (i.e. 36 months after surgery). In contrast, out of 59 patients whose PBMCs showed an increase in their PHA-induced proliferation within the first 12 months after surgery, only one (2%) presented with disease progression. We thus conclude that PHA-induced proliferation of PBMCs derived from patients with breast cancer depends upon the tumour load and is a good clinical predictor for the further course of the disease.