Immunologic markers associated with favorable prognosis in breast cancer patients: Role of innate immune system.

2011 ◽  
Vol 29 (27_suppl) ◽  
pp. 43-43
Author(s):  
M. L. Ascierto ◽  
M. Kmieciak ◽  
M. O. Idowu ◽  
D. Bedognetti ◽  
A. De Maria ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Nk Cells ◽  
Nk Cell ◽  
Breast Cancer Patients ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Favorable Prognosis ◽  
Cell Target

43 Background: Recognition of tumor cells by NK cells is mediated by the interaction of activating and inhibitory NK cell receptors with ligands expressed on the interacting cell. In addition to inhibitory and activating receptors, NK cells express adhesion molecules that allow conjugate formation between NK cells and their tumor targets. We have recently identified by transcriptional analysis of breast tumor specimens a signature of 5 genes, which included B cell response and interferon signaling, found to predict with > 85% accuracy relapse-free survival. In the current study we analyzed by gene expression profile, whether a differential expression of activatory and inhibitory receptors and gene involved in NK cell-target interactions could be identified in relapse and relapse free patients.Methods: RNA extraction and gene expression analysis was performed on tumor specimens with at least 10% of infiltrating cells deriving from 9 from breast cancer patients who had either 3-7 years relapse-free survival (n=9) or developed tumor relapse within 1-3 years after the initial treatment (n=8). Data were analyzed by BRB tools and Partek software.Results: Our results showed that patients with a favorable prognosis showed increased expression of genes involved in NK interaction with tumor cells and NK activating signaling. In particular an up-regulation of leukocyte function-associated antigen 1 (LFA-1) gene, typically involved in NK cells adhesion to target cells and DNAM 1, usually associated with activation of NK cells and considered one of the major protagonist of NK- Dendritic cells crosstalk, was observed to occur in relapse free patients. In addition, an up regulation of CD96 and CRTAM which, like DNAM 1, promote NK cell-target cell adhesion by interacting with the Necl2 and poliovirus receptor (PVR), was observed in relapse free patients. Conclusions: Our observation suggests that the NK signatures are associated with favorable outcome in breast cancer and allow us to generate new hypothesis on the role of innate immunity in this contest.

Involvement of NK cell molecular signatures in favorable prognosis of breast cancer patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10565-10565
Author(s):  
Maria Libera Ascierto ◽  
Michael O Idowu ◽  
Yingdong Zhao ◽  
Davide Bedognetti ◽  
Paolo Antonio Ascierto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Nk Cells ◽  
Cancer Patients ◽  
Adhesion Molecules ◽  
Nk Cell ◽  
Breast Cancer Patients ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Favorable Prognosis ◽  
Activating Receptors

10565 Background: Tumor cell recognition by NK cells is mediated by the interaction of activating and inhibitory NK cell receptors with their ligands expressed on tumor cells. In addition, NK cells express adhesion molecules that facilitate formation of the immunological synapse with the tumor targets. Here, we investigated whether the coordinate expression of NK activating receptors and adhesion molecules could provide a signature to segregate breast cancer patients into relapse and relapse-free outcomes. Methods: Gene expression profiling, RT-PCR screening and survival analysis were performed on RNA extracted from primary breast cancers. Tumors were obtained from patients experiencing either 5-8 years relapse-free survival or tumor relapse within 1-3 years following initial treatment. Results: Tumors from patients with a favorable prognosis were characterized by increased expression of genes involved in NK cell interaction with tumor cells and its activation signaling. In particular, up-regulation of Natural Cytotoxicity Receptors (NCRs), leukocyte function-associated antigen 1 (LFA-1), CD226 (DNAM-1) and CD96 was observed in relapse-free patients. Thus, the expression of the NK activating receptors and relevant adhesion molecules involved in NK cell:target interactions can predict relapse free survival in breast cancer patients. Conclusions: Results from the present study, highlighted the effector cooperation between the innate and adaptive immune components within the tumor microenvironment. The NK cells parameters identified in this study, together with the prognostic B and T cell signatures previously reported by us, represent a powerful tool for predicting breast cancer outcome which might be easily introduced in clinical practice.

scholarly journals Prognostic impact of the glypican family of heparan sulfate proteoglycans on the survival of breast cancer patients

2021 ◽  
Author(s):  
Paulina Karin Grillo ◽  
Balázs Győrffy ◽  
Martin Götte
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Heparan Sulfate ◽  
Cancer Patients ◽  
Heparan Sulfate Proteoglycans ◽  
Prognostic Impact ◽  
Breast Cancer Patients ◽  
Relapse Free Survival ◽  
Free Survival ◽  
The Impact

Abstract Purpose Dysregulated expression of proteoglycans influences the outcome and progression of numerous cancers. Several studies have investigated the role of individual glypicans in cancer, however, the impact of the whole glypican family of heparan sulfate proteoglycans on prognosis of a large patient cohort of breast cancer patients has not yet been investigated. In the present study, our aim was to investigate the prognostic power of the glypicans in breast cancer patients. Methods We used a public database including both gene expression data and survival information for 3951 breast cancer patients to determine the prognostic value of glypicans on relapse-free survival using Cox regression analysis. Moreover, we performed quantitative Real-Time PCR to determine glypican gene expression levels in seven representative breast cancer cell lines. Results We found that high GPC3 levels were associated with a better prognosis in overall breast cancer patients. When stratified by hormone receptor status, we found that in worse prognosis subtypes low GPC1 levels correlate with a longer relapse-free survival, and in more favorable subtypes low GPC6 was associated with longer survival. Conclusion Our study concludes that glypicans could act as subtype-specific biomarkers for the prognosis of breast cancer patients and sparks hope for future research on glypicans possibly eventually providing targets for the treatment of the disease.

scholarly journals Molecular signatures mostly associated with NK cells are predictive of relapse free survival in breast cancer patients

2013 ◽  
Vol 11 (1) ◽  
pp. 145 ◽  
Author(s):  
Maria Ascierto ◽  
Michael O Idowu ◽  
Yingdong Zhao ◽  
Hanif Khalak ◽  
Kyle K Payne ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Nk Cells ◽  
Cancer Patients ◽  
Molecular Signatures ◽  
Breast Cancer Patients ◽  
Relapse Free Survival ◽  
Free Survival

Effective Alloreactive NK Cell Therapy for Breast Cancer In Mice Requires Conditioning with Cyclophosphamide and Total Body Irradiation but Not Bone Marrow Engraftment

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2085-2085
Author(s):  
Michel Van Gelder ◽  
Peter Frings ◽  
Catarina Matos ◽  
Harry C. Schouten ◽  
Gerard M.J. Bos
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Nk Cells ◽  
Nk Cell ◽  
Spleen Cells ◽  
Slow Cycling ◽  
4T1 Breast Cancer ◽  
Bone Marrow Engraftment

Abstract Abstract 2085 Background: Patients with metastasized breast cancer cannot be cured by current standard treatment options. One hypothesis is that slow cycling chemo-resistant tumor stem cells give rise to new tumors after cytoreductive treatment, ultimately leading to chemoresistant tumors. Last year we showed that the 4T1 mouse breast cancer model contains slow-cycling chemo-resistant cells that induce renewed growth of the tumor after chemo- and radiotherapy (abstract 4082). We also showed that haploidentical spleen and bone marrow transplantation (BMT) cures the mice and that donor NK cells are a prerequisite. Our current aim was to study the need of long term BM engraftment and to study the role of the conditioning in the curative process. Methods: The 4T1 breast cancer cell line, originating from a spontaneous Balb/c (H-2d) breast cancer, was cultured under standard conditions. Fifty thousand 4T1 cells were injected s.c. in the flank. For the experiments addressing the need for haploidentical BMT tumor bearing CB6F1 (H-2b/d) recipients were treated with 2x 2Gy total body irradiation and 200 mg/kg cyclophosphamide (CY+TBI) followed by in vitro NK cell enriched haploidentical B6CBAF1 (H-2b/k) spleen cell infusion with or without additional BM cells. Chimerism in tumor-free surviving recipients was measured by flowcytometry of spleens at least 100 days after the treatment. The role of the conditioning in the alloreactive NK cell effect was studied in fully H-2 mismatched B6CBAF1 mice. When indicated, in vivo NK cell depletion was by i.p. injection of anti-AsialoGM1. Results: Figure A shows overall survival of mice with breast cancer after various treatments (10 mice per group). Haploidentical BMT plus spleen cells cured 50% of tumor bearing mice after CY+TBI (♦, dashed line) and survival was at least as good when NK cell enriched spleen cells were co-transplanted (▴, solid line). Transplantation of spleen cells from NK cell depleted mice (•, dotted line) obliterated the beneficial effect of haploidentical transplantation and resulted is similar poor survival as syngeneic BMT plus spleen cells (▪, solid line). The majority of mice that received NK cell enriched spleen cells (10 out of 14 tested) had no bone marrow engraftment and in the other four only 1–5% donor cells were detectable at 150 days. Recipients of unmanipulated haploidentical spleen and BM cells had >90% donor chimerism in 10 out of 14 tested. The cure rate in both groups was nevertheless similarly high. In a subsequent experiment (Figure B, 10 mice per group) we infused haploidentical NK cells only after CY+TBI (▴, solid line); other groups received T cell depleted (x, solid line) or T cell replete (♦, solid line) haploidentical BMT, or syngeneic BMT (▪, solid line). This resulted in a similar superior tumor-free survival (80-90%) than in mice co-transplanted with haploidentical BM (90%), as compared with syngeneic BM and spleen cell transplantation (•, dotted line). We then planned to study the role of the conditioning in the curative process. For this purpose 4T1 breast cancer cells were injected in fully H-2 mismatched B6CBAF1 mice (H-2b/k). Surprisingly, 4T1 breast cancer is not rejected by B6CBAF1 mice despite the full MHC mismatch. Tumors are only rejected when the mice were treated with CY+TBI. Tumor rejection proved to be NK cell dependant and not a direct result of the conditioning as it was prevented by in vivo NK cell depletion. Conclusions: This report provides the first evidence that chemo resistant tumor cells can be eliminated in vivo by alloreactive NK cells resulting in cure without the need for long term donor bone marrow engraftment. Conditioning with CY+TBI seems essential for this effect. These results set the stage for the exploration of alloreactive NK therapy in patients with metastasized breast cancer. Disclosures: No relevant conflicts of interest to declare.

Prognostic significance of immunohistochemical expression of Rb gene product in operable breast cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21121-21121
Author(s):  
H. Song ◽  
Y. Do ◽  
S. Gang ◽  
S. Kwon ◽  
S. Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Gene Product ◽  
Prognostic Significance ◽  
Breast Cancer Patients ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Node Metastasis ◽  
Rb Gene

21121 Background: The aim of this study was to investigate the prognostic significance of the expression of Rb gene product in operable invasive breast cancer by performing immunohistochemical analysis. Methods: Between January 1993 and December 2001, 212 operable invasive breast cancer patients underwent immunohistochemical staining for Rb, and we retrospectively analyzed these results together with the clinical outcomes. Results: The overexpression of p53 was detected in 72.7% of the cases. The overexpression of Rb was correlated with positive hormonal receptor (p=0.000), and inversely correlated with lymph node metastasis (p=0.017) and vascular invasion (p=0.004). The tumor size, tumor histology, histologic grade, and tumor stage were not related to the overexpression of p53. Multivariate Cox regression analysis indicate that lymph node metastasis and tumor size were the significant prognostic factors for overall survival; lymph node metastasis was the significant prognostic factor for relapse free survival. On the subgroup analysis, the Rb expressors showed better 7-year overall survival (98.5% vs. 81.5%, respectively, p=0.005) and relapse free survival (94.1% vs. 77.4%, respectively, p=0.021) than did the p53 non-overexpressors for the patients without lymph node metastasis. However, for the patients with lymph node metastasis, the survival rates were not different for both the Rb expressors and the Rb non-expressors. Conclusions: Immunohistochemical staining of the Rb gene product was an independent prognostic factor for predicting survival of the lymph node negative operable breast cancer patients. No significant financial relationships to disclose.

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