Dendritic cells are defective in breast cancer patients: a potential role for polyamine in this immunodeficiency

INTRODUCTION: Dendritic cells (DCs) are antigen-presenting cells that are currently employed in cancer clinical trials. However, it is not clear whether their ability to induce tumour-specific immune responses when they are isolated from cancer patients is reduced relative to their ability in vivo. We determined the phenotype and functional activity of DCs from cancer patients and investigated the effect of putrescine, a polyamine molecule that is released in large amounts by cancer cells and has been implicated in metastatic invasion, on DCs. METHODS: The IL-4/GM-CSF (granulocyte–macrophage colony-stimulating factor) procedure for culturing blood monocyte-derived DCs was applied to cells from healthy donors and patients (17 with breast, 7 with colorectal and 10 with renal cell carcinoma). The same peroxide-treated tumour cells (M74 cell line) were used for DC pulsing. We investigated the effects of stimulation of autologous lymphocytes by DCs pulsed with treated tumour cells (DC-Tu), and cytolytic activity of T cells was determined in the same target cells. RESULTS: Certain differences were observed between donors and breast cancer patients. The yield of DCs was dramatically weaker, and expression of MHC class II was lower and the percentage of HLA-DR(-)Lin(- )cells higher in patients. Whatever combination of maturating agents was used, expression of markers of mature DCs was significantly lower in patients. Also, DCs from patients exhibited reduced ability to stimulate cytotoxic T lymphocytes. After DC-Tu stimulation, specific cytolytic activity was enhanced by up to 40% when DCs were from donors but only up to 10% when they were from patients. IFN-γ production was repeatedly found to be enhanced in donors but not in patients. By adding putrescine to DCs from donors, it was possible to enhance the HLA-DR(-)Lin(- )cell percentage and to reduce the final cytolytic activity of lymphocytes after DC-Tu stimulation, mimicking defective DC function. These putrescine-induced deficiencies were reversed by treating DCs with all-trans retinoic acid. CONCLUSION: These data are consistent with blockade of antigen-presenting cells at an early stage of differentiation in patients with breast cancer. Putrescine released in the microenvironmement of DCs could be involved in this blockade. Use of all-trans retinoic acid treatment to reverse this blockade and favour ex vivo expansion of antigen-specific T lymphocytes is of real interest

Immunité anti-tumorale et thérapies cellulaires du cancer

L’existence de lymphocytes T capables de reconnaître des antigènes spécifiques des tumeurs est maintenant complètement admise. Ces cellules, ainsi que les cellules natural killer (NK), infiltrent le tissu tumoral et sont en mesure d’exercer une cytotoxicité à l’égard des cellules cancéreuses. Cependant, au cours de l’histoire naturelle du développement tumoral, la réponse immunitaire se révèle inefficace. Ce constat est à l’origine de nombreux travaux de recherche dont l’objectif à terme est de concevoir de nouvelles approches thérapeutiques du cancer. L’immunothérapie a fait la preuve de son efficacité sur des modèles expérimentaux de tumeur chez l’animal. La thérapie cellulaire du cancer par cellules immunocompétentes est actuellement en évaluation clinique. Dans ces stratégies thérapeutiques, deux approches sont en évaluation : stimuler in vivo le développement d’une immunité protectrice, à l’aide de cellules présentatrices d’antigènes, ou encore apporter au patient des cellules effectrices éduquées in vitro.The identification of tumor specific antigens has provided important advance in tumor immunology. It is now established that specific cytotoxic T lymphocytes (CTL) and natural killer cells infiltrate tumor tissues and are effector cells able to control tumor growth. However, such a natural antitumor immunity has limited effects in cancer patients. Failure of host defenses against tumor is consecutive to several mechanisms which are becoming targets to design new immunotherapeutic approaches. CTL are critical components of the immune response to human tumors and induction of strong CTL responses is the goal of most current vaccine strategies. Effectiveness of cytokine therapy, cancer vaccines and injection of cells improving cellular immunity have been established in tumor grafted murine models. Clinical trials are underway. To day, interest is particularly focused on cell therapy : injected cells are either « ready to use » effector cells (lymphocytes) or antigen presenting cells able to induce a protective immune reaction in vivo (dendritic cells). The challenge ahead lie in the careful optimization of the most promising stategies in clinical situation

The prognostic value of erythrocyte polyamines in the preoperative evaluation of patients with renal cell carcinoma.

International audienceINTRODUCTION: Polyamines, spermine and spermidine, are ubiquitous polycationic structures, which are essential for cell proliferation and differentiation. We tested whether spermine and spermidine could improve the prognostic ability of six established preoperative predictors of cancer-specific mortality (CSM) after partial or radical nephrectomy for renal cell carcinoma (RCC). MATERIALS AND METHODS: Overall, 385 patients with clinical stages T(1-3), M(0-1) RCC were treated with radical or partial nephrectomy at a single institution between 1990 and 2007. Kaplan-Meier plots depicted CSM after stratification according to spermine and spermidine levels (dichotomised to above and below the median value). Univariable and multivariable Cox regression models tested the prognostic ability of continuously coded spermine and spermidine levels in preoperative CSM predictions. Covariates consisted of pre-treatment T stage, M stage, age, gender and symptom classification. RESULTS: The 5-year CSM-free survival of patients with spermine levels 4.5 nmol/8x10(9) erythrocytes were, respectively, 79.5% and 65.0%. Similarly, the 5-year CSM-free survival of patients with spermidine levels 9.0 nmol/8x10(9) erythrocytes were, respectively, 81.1% and 63.7%. In multivariable analyses addressing CSM after surgery, both spermine (p< or =0.002) and spermidine (p< or =0.001) achieved independent predictor status and improved the accuracy of established preoperative CSM predictors by 2.1% (p<0.001). CONCLUSIONS: Circulating polyamine levels may significantly improve the prognostic value of established determinants of CSM in patients with RCC of all stages prior to nephrectomy. External validation of our findings is required prior to implementation in clinical practice

Valeur pronostique des polyamines érythrocytaires dans le cancer du rein. Étude chez 418 patients [Prognostic value of erythrocyte polyamines levels in renal cell carcinoma. Prospective study in 418 cases]

International audienceOBJECTIVES: Polyamines: Spermine (Spm) and Spermidine (Spmd), are essential for cell proliferation and differentiation. A measurement of erythocytes polyamines (EPA) was developed in our institution. Our objective was to evaluate this marker as a new prognostic factor in renal cell carcinoma. PATIENTS AND METHODS: A blood sample was prospectively taken before surgery, among 418 patients who had an enlarged nephrectomy (n=318) or a partial nephrectomy (n=100) to quantify EPA rates by using the HPLC technique. The qualitative and quantitative variables have been compared using chi(2) and Student statistical analyses. The survivals have been normalized by the Kaplan Meier and Cox methods. RESULTS: The average age of our population was 64 years (21-88). The average decline was 41 months (1-214). The median size of tumors was 6.5cm (1-24). The median rate of Spm and Spmd were respectively 4.7 (1-83) and 9 (2-86)nmol/8.10(9) erythrocytes. Spm and Spmd were linked to the T stage (p=0.001), and the ECOG (p=0.001 and 0,008). Spm was not linked at N and M stages but at the Fuhrman grade (p=0.001). Spmd was linked to the N, M stages (p=0.04). With univariate analysis, the tumor diameter, the TNM stage, the Fuhrman grade as well as Spm and Spmd (p<0.0001) were predictors of specific survival. With multivariate analysis, some prognostic factors remained independent: the TNM stage, the ECOG and Spmd, a continuous variable (p=0.0001), pushing the rank of Fuhrman out of the model. When Spm and Spmd were dichotomized in quantitative variables, they were both independent factors. CONCLUSION: The EPA is a new prognostic tool, before surgery, which will be tested for its integration into prognostic normograms