Antitumor activity of pleural cavity macrophages and its regulation by pleural cavity lymphocytes in patients with lung cancer

Antitumor activities of pleural cavity macrophages (PCM) and pleural cavity lymphocytes (PCL) in lung cancer patients were examined. The effect of coculture supernatants of PCL and autologous tumor cells on the cytostatic activity of macrophages was also examined. Cytostatic activity of PCM was not affected by an advance of metastasis to regional lymph nodes or increase of tumor size and difference of histological type. However, the cytostatic activity of PCM was markedly augmented when pleural invasion was limited to within the visceral pleura although it was low when pleural invasion was absent or extended beyond the visceral pleura. On the other hand, PCL did not exert any cytolytic activity against various tumor target cells. However, coculture supernatants of PCL and autologous tumor cells exhibited the activity of macrophage-activating factor against guinea pig peritoneal macrophages. Furthermore, the higher the cytostatic activity of PCM, the higher the macrophage-activating factor activity of the coculture supernatant of PCL and autologous tumor cells was. These results suggested that antitumor activity of PCM was controlled by specifically sensitized PCL through lymphokines.     

Peripheral blood natural killer cell activity in human breast cancer patients and its modulation by T-cell growth factor and autologous plasma

The role of clinical status and chemotherapeutic intervention on native and inducible natural killer cell (NK) activity in breast cancer was ascertained by determining the K562 cytotoxicity capacity of peripheral blood lymphocytes. The level of NK activity in breast cancer patients receiving chemotherapy (n = 62) was significantly lower than that observed in patients currently receiving no treatment (n = 56) (at effector: target [E:T] ratios of 20:1, 10:1, and 5:1, 23.8%, 17.9%, and 12.1% versus 34.9%, 25.6%, and 15.9%, respectively; P less than 0.01, two-way analysis of variance). The absolute level of NK activity in peripheral blood of cancer patients on therapy was further reduced when compared with untreated patients and healthy controls when reductions in lymphocyte counts concomitant with chemotherapeutic intervention were included in calculations of NK activity. T-cell growth factor (TCGF) increased NK activity in all breast cancer patients and healthy controls with maximal stimulation of basal activity at a concentration of 10% (volume/volume [v/v]) TCGF. The percent stimulation of basal NK activity by TCGF was significantly greater in patients receiving chemotherapy (26.4%, 24.3%, and 19.0% at an E:T of 20:1, 10:1, and 5:1, respectively; n = 23) than in untreated patients (16.6%, 18.5%, and 18.9%; n = 21) and healthy controls (23.5, 18.6, and 8.1; n = 8) (P less than 0.05 and P less than 0.01, respectively, two-way ANOVA). The influence of soluble factors and agents in serum on peripheral blood NK activity was assessed by monitoring the effects of autologous plasma on basal and TCGF-stimulated NK activity. Autologous plasma at concentrations less than or equal to 10% (v/v) enhanced basal NK activity. Levels of inducible NK activity in the presence of either 10% TCGF, 5% plasma, or a combination of both were not significantly different in statistical comparisons of both the effects of inducer and therapeutic modality. At concentrations of plasma greater than 10% (v/v), progressively decreasing NK activities were observed. T-cell growth factor could partially reverse the inhibitions of NK activity by 25% autologous plasma. In 13 experiments, basal NK activity and NK activity in the presence of 10% TCGF, 25% autologous plasma, and a combination of TCGF and plasma were 27.6%, 46.0%, 16.3%, and 28.1%, respectively (E:T = 20:1). This study indicates that NK function is compromised in breast cancer patients receiving cytotoxic drug-therapy. The potential use of TCGF in adjuvant immunotherapy as a modulator of NK function has been demonstrated.(ABSTRACT TRUNCATED AT 400 WORDS)     

Deficient superoxide-generating activity and its activation of blood monocytes in cancer patients

Superoxide (O2-)-generating activity of blood monocytes, the precursors of macrophages, from patients with advanced cancer and/or infection was studied. Monocytes from normal subjects generated 0.288 +/- 0.022 nmol O2-/min/10(5) cells (mean +/- S.E.M., n = 36) after sequential stimulation with cytochalasin E and wheat germ agglutinin. Monocytes from 69 non-infected adult patients with advanced malignancy of the stomach, esophagus and liver, and 7 pediatric patients with neoplastic disease released significantly less O2- than those from normal subjects (0.176 +/- 0.015, P less than 0.005). Infection increased the activity about 4-fold in patients with malignancy compared to non-infected cancer patients. These results suggest that monocytes of cancer patients are defective in secreting O2-, though the activity may be stimulated by infection.     

Interleukin-2 induces cytotoxic activity in lymphocytes from regional axillary nodes of breast cancer patients

Natural killer (NK) cells and lymphokine-activated killer (LAK) cells have been involved in immunosurveillance against tumors. A normal NK activity was observed in peripheral blood (PB) mononuclear cells (MNC) from women with breast cancer, but a very low or absent NK cytotoxicity was found in the regional lymph node (RLN) MNC. However, strong cytotoxic activity against NK-resistant and NK-sensitive target cells can be induced in RLN MNC by long-term (5-day) incubation with recombinant interleukin-2 (rIL-2). This cytotoxic inducer effect of rIL-2, not observed with recombinant interferon gamma, was dose and time-dependent and was not associated with modifications in the low number of Leu 11+ or Leu 7+ cells present in the population. Both the lack of NK activity and the generation of rIL-2-activated killer cells can be readily demonstrated in either histologically affected or unaffected RLN. These results stress the value of the immunomodulators inducing cytotoxic activity in RLN MNC of patients with tumors, and are discussed in association with their possible therapeutical role.     

Interleukin-12 augments cytolytic activity of peripheral blood mononuclear cells against autologous lung cancer cells in combination with IL-2

The majority of patients with advanced lung cancer die within a few years. Accordingly, new therapeutic modalities need to be developed. Interleukin (IL)-12 was previously known as natural killer (NK) cell stimulatory factor or cytotoxic lymphocyte maturation factor. By virtue of its effects on T cells and NK cells, IL-12 seems to be one of the key cytokines that regulates cell-mediated anti tumor immune responses. Recently, there has been a substantial interest in the potential applications of IL-12 in the treatment of lung cancer. However, there have been no reports about the effect of IL-12 on peripheral blood mononuclear cells (PBMCs) obtained from lung cancer patients in an autologous setting. In this study, we examined the cytotoxicity of PBMC activated by IL-2, IL-12 or both against K562 or autologous lung cancer cells. In contrast to the effect of IL-2 on NK activity, IL-12 alone augmented NK activity against K562 cells, but not against autologous lung cancer cells. IL-12 augmented the IL-2 mediated cytotoxicity of PBMC against both K562 and autologous lung cancer cells. In the absence of IL-2, IL-12 alone cannot induce an autologous anti-tumor effect in vivo. In summary, our results clearly demonstrated that IL-12 can augment the cytolytic activity of PBMC against K562 and autologous lung cancer cells when combined with IL-2, although, IL-12 alone was unable to induce a marked increase in the cytotoxicity against autologous lung cancer cells. These results suggest that an administration of IL-12 in combination with IL-2 may be a useful therapeutic option for solid tumors.     

Induction of killer cells from lymphocytes in pleural effusion of advanced lung cancer patients

We analyzed the phenotype and cytotoxic ability of pleural exudative lymphocytes (PLEL) which were obtained from 18 advanced lung cancer patients. Freshly isolated PLEL were mainly CD4(+) T cells and had weak natural killer, autologous tumor killing and lymphokine-activated killer activities. After cultivation of PLEL with interleukin-2, cytotoxicity of PLEL against autologous tumor cells was increased at 2 weeks, but it was remarkably reduced at 4 weeks. When PLEL were stimulated by mitomycin C-treated autologous tumor cells during culture, autologous tumor killing activity of PLEL was significantly enhanced even after 4 weeks of cultivation. Cold target inhibition analysis and binding inhibition assays using monoclonal antibodies indicated that autologous tumor stimulation could induce major histocompatibility complex class I restricted cytotoxic T lymphocytes specific for autologous tumor cells in some cases.     

Interleukin-2 activity and the response of peripheral blood lymphocytes in patients with gynecologic malignancies

The interleukin-2 (IL-2) production in peripheral blood lymphocytes (PBL), the response to IL-2, and the IL-2 absorption by PBL was studied in 34 patients with gynecologic malignancies. In addition measurement of the OKT 4/8 cell ratios were made. The OKT 4/8 cell ratio in patients with advanced gynecologic malignancies was significantly lower than that in patients with benign tumor. PBL from advanced cancer patients activated by phytohemagglutinin (PHA) had significantly lower IL-2 productivity than that from patients with benign tumors, while no significant difference was observed in its abilities to respond to IL-2 and to absorb IL-2. The OKT 4/8 cell ratio and IL-2 productivity in PBL of patients with good prognosis were significantly elevated after chemotherapy. On the other hand, PBL of patients with poor prognosis declined to about one-half of the preoperative levels. Although in patients with good prognosis the ability of PBL to respond to IL-2 was not changed before and after treatment, in patients with poor prognosis the response was significantly increased after chemotherapy. However, the ability to absorb IL-2 was not affected by treatment.     

Beneficial effects of interleukin-2 on natural killer activity in lung cancer patients

The effects of human interleukin-2 (IL-2) on the growth and natural killer (NK) activities of lymphocytes were evaluated in patients with advanced lung cancer, and compared with age-matched normal subjects. Peripheral blood lymphocytes (PBL) from the patients and the controls were grown exponentially in response to IL-2 and showed no differences in the cell numbers and the proliferative capacities. In both groups, pretreatment for 18 hr with IL-2 was able to augment the NK activity of PBL. Furthermore, PBL propagated in IL-2 over a period of 15 days also demonstrated vigorous NK activity, although there was a relative broad range of NK levels among those from the patient individuals. The present study suggests that the depressed NK activity of PBL from our patients can not be explained by lack of their responsiveness to IL-2, and that human IL-2 can augment the NK activity of PBL and support the growth of PBL-derived cells with high NK levels in patients with lung cancer.     

Lymphokine-activated killer activity of tumor-associated and peripheral blood lymphocytes isolated from patients with ascites ovarian tumors

Peripheral blood lymphocytes (PBLs) and tumor-associated lymphocytes (TALs) were isolated from 36 patients with advanced ovarian adenocarcinoma and peritoneal effusions for study of lymphokine-activated killer activity. PBLs and TALs cultured in vitro for 3-5 days in the presence of interleukin-2 (IL-2, supernatant of the MLA 144 gibbon cell line, or human recombinant IL-2) expressed higher levels of cytotoxicity as compared to cells cultured in medium alone, against natural killer (NK)-susceptible (K562) or NK-resistant targets (Daudi and the human ovarian carcinoma cell line SW626). When ovarian tumor cells, freshly isolated from carcinomatous ascites or surgical specimens, were used as target cells in the cytotoxicity assay, 8 of 14 PBLs and 5 of 7 TAL preparations lysed the autologous tumor after treatment with IL-2, while no spontaneous reactivity was observed in any of the 14 patients tested. Although levels of lysis were usually relatively low, these data demonstrate that PBLs and TALs from ovarian cancer patients (TALs usually exhibiting low NK activity) when stimulated in vitro by IL-2 acquire some cytotoxic potential against the autologous tumor.     

自体细胞因子诱导的杀伤细胞治疗肺癌患者的临床疗效观察

目的 评估CIK细胞(Cytokine-induced killer cell,CIK)治疗晚期肺癌的临床疗效。方法 从32例晚期肺癌患者外周血中分离出单个核细胞(PBMC),加入含有IFN-γ、IL-2和抗CD3单抗等细胞因子的培养基进行培养,培养15天后分次回输给患者。观察患者治疗前后瘤体变化、免疫指标变化、临床症状的改善情况和毒副反应,进行临床疗效评价。结果 32例接受CIK治疗的患者临床症状明显改善,毒副反应轻。免疫表型分析结果 显示CD3/CD4共表达34.4%,CD3/CD8共表达68.2%,CD3/CD56共表达13.7%。CIK细胞回输后约15天CT影像显示胸腔积液减少。临床疗效评价有效率为56.0%,疾病控制率(CR+PR+SD)为84.3%。结论 CIK细胞免疫疗法可以改善肺癌患者免疫功能,抑制肿瘤生长,改善临床症状,改善生存质量。     

Superoxide anion-generating activity of polymorphonuclear leukocytes and monocytes in patients with lung cancer.

Superoxide anion (O2-) production by polymorphonuclear leukocytes (PMN) and monocytes (MN) was measured in the peripheral blood of 70 patients with lung cancer. The O2- production by these cells was decreased in many, but not all, patients. The incidence of patients with lower O2- production increased as the stage advanced. The correlation between O2- production by these cells and peripheral blood smears was evaluated in patients with cancer. Patients with 80% granulocytes and 40% monocytes or more in their peripheral blood had a significantly lower O2- production by PMN and MN compared with those with less than 80% granulocytes and 40% monocytes, respectively. These results indicate that an abnormally increased number of granulocytes and monocytes in the peripheral blood of patients with cancer may depress immunoregulatory function. In addition, decreased O2- production by these cells should be considered when assessing the defense mechanisms and susceptibility to infection of these patients.     

Tumor necrosis factor-alfa production by monocytes from lung and colorectal cancer patients

Tumour necrosis factor-alpha (TNF-alpha) is a monocyte (MO)-derived cytokine that plays an essential role in the immunological system. In the present study our aim was to evaluate the levels of TNF-alpha secreted by MO from cancer patients. Blood MO were obtained from 10 lung cancer patients (LCP), 10 colorectal cancer patients (CCP) and 10 healthy donors (HD). TNF-alpha levels in MO culture supernatants spontaneously (sp) secreted or after stimulation with LPS treatment were evaluated using a commercial ELISA kit (sensibility: 10-1000 pg/ml). Mean values, expressed as pg/ml were: LCP: sp= 452.6+/-107.2, LPS= 589.5+/-126.7); CCP: sp= 84.1+/-25.0, LPS= 437.3+/-93.2; HD: sp= 74.2+/-21.5, LPS= 573.5+/-87.1. We concluded that MO from LCP secrete high levels of TNF-alpha spontaneously (p< 0.003 versus HD) and it was also observed an absence of response to LPS treatment in the 33% of the cases in these patients.     

Significance of cytotoxic activity of peripheral blood lymphocytes against autologous tumor cells in patients with bladder cancer

Cell-mediated immunity is an important and central mechanism of host resistance to cancer. Most reported studies have used cultured tumor cell lines as targets to assess antitumor cell-mediated cytotoxicity. However, it is difficult to translate the data generated from the cytotoxic activity against cultured tumor cell lines to cytotoxicity against autologous tumors. In a recent study, we have reported on the prognostic significance of circulating cytotoxic lymphocytes against autologous tumor cells in patients with bladder cancer. In this study, we examined whether established bladder cancer cell line like T24 or NK-sensitive K562 target cells can be substituted for autologous bladder cancer cells. The cytotoxic activity of peripheral blood lymphocytes (PBL) against freshly isolated autologous tumor cells, the T24 human bladder cancer cell line and the NK-sensitive K562 human myelogenous leukemia cell line was studied in 63 patients with primary initial bladder cancer by a 12-h 51Cr release assay. The mean percent cytotoxic activity of PBL directed against autologous tumor cells, T24 cells and K562 cells were 11.3%, 18.2% and 29.4%, respectively, using an E:T of 40:1. The cytotoxic activity against T24 cells in patients with bladder cancer was higher than that in normal individuals. The anti-K562 and the anti-T24 cytotoxic activities in patients with low-stage or low-grade bladder cancer were relatively higher than those in patients with high-stage or high-grade cancer, but not statistically significant. There was no correlation between the anti-autologous tumor cytotoxic activity and either the histologic grade or stage in patients with bladder cancer. The extent of the anti-autologous tumor cytotoxic activity was not paralleled with that of either the anti-K562 or the anti-T24 cytotoxic activity. In contrast, the anti-K562 cytotoxic activity correlated positively with the anti-T24 cytotoxic activity. Separation of PBL revealed that the anti-K562 and the anti-T24 cytotoxic activities were mediated mainly by the NK cells, whereas the anti-autologous tumor cytotoxic activity was mediated by both the NK cells and the T lymphocytes. These findings demonstrate that cytotoxicity against T24 or K562 cells is not of prognostic value. The magnitude of the anti-autologous tumor cytotoxic activity of PBL derived from bladder cancer patients might represent an independent and important immunological parameter to monitor disease progression.     

Prediction of postoperative clinical course by autologous tumor-killing activity in lung cancer patients

Fifty patients with primary localized lung cancer were tested at the time of surgery for the ability of their lymphocytes to kill autologous, freshly isolated tumor cells, and the assay was evaluated for prognostic significance. Peripheral blood lymphocytes of 27 patients (54%) demonstrated significant autologous tumor-killing activity in 6-hour 51Cr-release assays. Twenty-three of the 27 patients with autologous tumor-killing activity remained tumor free and survived more than 5 years after curative surgery, while all 23 who were negative for autologous tumor-killing activity relapsed by 18 months after surgery and died within 42 months after surgery. The differences in survival curves for the two groups were highly significant (P less than .00003). Autologous tumor-killing activity was not correlated with natural killer (NK) cell activity against K562 human myeloid leukemia cells or proliferation of lymphocytes stimulated with autologous, freshly isolated tumor cells in mixed culture. There were no differences in total survival between patients with positive results and those with negative results in tests of NK cell activity and autologous mixed lymphocyte-tumor culture reaction. These results indicate that autologous tumor-killing activity is a meaningful prognostic indicator and provide evidence for immunological control of tumor growth and metastasis. According to our preliminary data, it is unlikely that lung cancer patients who remain tumor free after 60 months of follow-up will develop recurrence or die from the disease. We are conducting a study to determine whether induction of autologous tumor-killing activity before surgery, by treatment with biological response modifiers,can improve the clinical outcome in patients who do not naturally have this potential.     

Infiltration of interleukin-2-inducible killer cells in ascitic fluid and pleural effusions of advanced cancer patients

Using ascitic fluid or pleural effusion obtained from 13 ovarian or metastatic breast cancer patients, we separated tumor cells from effusion-associated lymphocytes (EAL) with Percoll density centrifugation. Lymphocytes were incubated with recombinant interleukin 2 (IL-2) for 3-4 days and then assessed for tumoricidal activity in a 51chromium-release assay. The IL-2-activated EAL were found to lyse autologous fresh tumor cells, as well as allogeneic fresh tumor cells and FMEX tumor cells, a melanoma cell line which is resistant to natural killer cell activity but is sensitive to lysis by lymphokine-activated killer cells. There was little or no tumoricidal activity seen in freshly isolated EAL or in EAL which were cultured in medium without IL-2. Phenotypically, the IL-2-activated EAL were largely CD3-, although some cytolytic activity was found in CD3+ populations. Also, most activity was found in cells positive for CD2 (OKT11) and CD16 (Leu 11b), and negative for the monocyte marker Leu M3. These results indicate that the activated cell types found in EAL were predominantly natural killer/lymphokine-activated killer-like with a small contribution from T-cells. Finally, EAL were readily activated by IL-2 in medium containing autologous effusion fluid, indicating that in situ activation of tumoricidal activity by IL-2 can occur in the face of potentially inhibitory substances or cells that may exist in the effusions. Direct introduction of IL-2 may therefore be a potential therapeutic modality of effusion-forming cancers.     

Comparative analysis of interleukin 15 and interleukin 2 for induction of killer activity and of type 2 cytokine production by mononuclear cells from lung cancer patients.

Interleukin (IL) 15 is a novel cytokine with IL-2-like activity. In this study, we examined the effect of IL-15 on induction of non major histocompatibility complex (MHC)-restricted killer activity and of type 2 cytokine production by peripheral blood and pleural mononuclear cells (MNCs), from 34 lung cancer patients and 20 control subjects. IL-15 induced significant killer activity in blood MNCs from lung cancer patients as well as control subjects against a small-cell lung cancer cell line (SBC-3). Effective killer induction by IL-15 was observed even in blood MNCs and pleural MNCs from the site of tumour growth in advanced lung cancer patients. IL-12 had an additive effect with a suboptimal dose of IL-15 in induction of killer activity. In the case of MNCs from lung cancer patients, IL-10 production was more prominent when cells were incubated with IL-2 than with IL-15. IL-5 production was observed in MNCs from lung cancer patients stimulated with IL-2, but not with IL-15. These observations suggest that IL-15, by virtue of its lesser induction of type 2 cytokine, may be a better candidate than IL-2 for lung cancer immunotherapy.     

Interleukin-1 beta and interleukin-6 release by peripheral blood monocytes in head and neck cancer.

In patients with advanced head and neck squamous cell carcinoma (HNSC), evidence of cell-mediated immunity and monocyte functional abnormalities has been reported. We studied the production of interleukin 1 beta (IL-1 beta) and interleukin 6 (IL-6) by peripheral blood monocytes from 22 patients with HNSC (12 larynx and ten oral cavity cancers) in comparison with monocyte cytokine production of age-matched healthy subjects. Pure monocytes were incubated with and without lipopolysaccharides (LPS) (10 micrograms ml-1) for 4 h at 37 degrees C and IL-1 beta and IL-6 concentrations were determined in supernatants by specific ELISA. There was no significant difference in IL-1 beta levels in monocyte supernatants from cancer in comparison to control subjects; conversely, a higher IL-6 production by unstimulated and LPS-activated cells from HNSC patients than from controls was found. No relationship was observed between cytokine production and cancer stage. The regression analysis evidenced a significant correlation between IL-1 beta and IL-6 monocyte-release in HNSC patients and in controls, so suggesting a possible autocrine control of IL-6 production by other cytokines.     

Induction of in vitro tumoricidal activity in alveolar macrophages and monocytes from patients with lung cancer

Human alveolar macrophages (AMs) and blood monocytes were obtained from 65 smoking and nonsmoking normal volunteers and 29 patients with lung cancer. The oxidative metabolic response of these cells was measured by superoxide anion production after incubation with lipopolysaccharide. In addition, tumoricidal activity of AMs and monocytes was assessed against [3H]thymidine-labeled tumor target cells. Smoking was associated with depressed AM superoxide anion responses in normals but not in patients. In contrast, smoking appeared to slightly elevate monocyte superoxide anion activity. AMs and monocytes exposed to lipopolysaccharide or recombinant gamma-interferon showed tumoricidal activity in all groups. Mean cytotoxicity values of smoking patients versus smoking normals and exsmoking patients versus nonsmoking normals were not significantly different. Smoking, however, in both patients and normals was associated with significantly (P less than 0.005) depressed AM cytotoxicity levels (less than 40%) compared to nonsmoking volunteers and exsmoking patients. Activated AMs from cancer patients and normals were cytotoxic against three different tumorigenic cell lines but not against a nontumorigenic line. No correlation between monocyte and AM cytotoxic activity within single individuals was found. We conclude that AM and monocytes from smoking and exsmoking patients can be activated after exposure to immunomodulators; however, smoking may be slightly suppressive to cytotoxic responses. These studies provide a rationale for clinical trials of immunomodulators in patients with lung cancer.     

Cytotoxic activity of autologous lymphocytes against lung cancer cells; correlation of prognosis and recurrence pattern

Cytotoxic activity of lymphocytes cultured in IL-2 against autologous primary lung cancer cells was studied in relation to curativity, prognosis and relapse rate. A total of 51 patients, 44 males and 7 females, consisting of those with adenocarcinoma (n = 27), squamous cell carcinoma (n = 19), large cell carcinoma (n = 2), small cell carcinoma (n = 1), lung sarcoma (n = 1), and carcinoid (n = 1), were evaluated. Pathological stages of the patients were stage I (n = 16), stage II (n = 1), stage III (n = 28), and stage IV (n = 6). Thirteen patients (25.5%) underwent curative surgery, 23 patients (45.1%) received relative curative surgery and 15 patients (29.4%) received non-curative surgery. The mean value of cytotoxic activity in the patients who received curative surgery was 34.7 +/- 15.3%, relative curative surgery 26.5 +/- 18.9%, and non-curative surgery 42.8 +/- 22.3%. Among the patients who underwent curative and relative curative surgery, 23 patients survived more than 2 years and 13 patients died of cancer recurrence. Mean value of cytotoxic activity in the former (36.7 +/- 15.9%) was significantly (p less than 0.01) higher than that in the latter (17.1 +/- 14.7%). Positive rate (percentage of patients whose CA exceeded 15%) of the former (86.9%) was also higher than that of the latter (46.1%). Comparison between the survival curves of the positive cases (CA 15.0%) and negative cases (CA less than 15.0%) revealed a significantly better prognosis for the former (generalized Wilcoxon test: W/square root VarW = 2.198). The mean cytotoxic activity in the cases of local recurrence (25.7 +/- 16.6%, n = 7) was higher (p less than 0.10) than that in the cases with distant metastases (9.3 +/- 6.3%).     

Interleukin-2 activated human killer lymphocytes: lack of involvement of interferon in the development of IL-2-activated killer lymphocytes

When cultured with native or recombinant interleukin-2 (IL-2) human small agranular lymphocytes acquire the ability to kill various tumor targets. The development of these IL-2 activated killer (IAK) cells, also known as LAK, is observed in the absence of antigen or mitogen. Interferons are known to augment the lytic effects of natural killer cells and cytolytic T lymphocytes. Our study was undertaken to examine the effect of human alpha, beta, and gamma interferons on the induction and the effector phase of IAK function. When cultured with small lymphoid cells IFN alone did not induce anti-tumor cytolytic activity in those lymphocytes. Despite their known anti-proliferative effects, none of the 3 IFN species at any concentrations tested inhibited the development of IAK activity when present during the entire culture period. IFN neither inhibited nor augmented the development of IAK cells under suboptimal conditions. Furthermore, activation of IAK cells was not affected by the presence of neutralizing antibodies to either alpha or gamma IFN. Post-activation exposure of IAK cells to IFN also failed to either augment or inhibit their lytic activity. Thus, neither endogenously generated nor exogenously added IFN had any effect on the IAK system, in contrast to their augmenting effects on NK cells and CTL.