Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2013

Open Access 01-12-2013 | Research

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

Authors: Maria Libera Ascierto, Michael O Idowu, Yingdong Zhao, Hanif Khalak, Kyle K Payne, Xiang-Yang Wang, Catherine I Dumur, Davide Bedognetti, Sara Tomei, Paolo A Ascierto, Anil Shanker, Harry D Bear, Ena Wang, Francesco M Marincola, Andrea De Maria, Masoud H Manjili

Published in: Journal of Translational Medicine | Issue 1/2013

Login to get access

Abstract

Background

Recent observations suggest that immune-mediated tissue destruction is dependent upon coordinate activation of immune genes expressed by cells of the innate and adaptive immune systems.

Methods

Here, we performed a retrospective pilot study to investigate whether the coordinate expression of molecular signature mostly associated with NK cells could be used to segregate breast cancer patients into relapse and relapse-free outcomes.

Results

By analyzing primary breast cancer specimens derived from patients who experienced either 58–116 months (~5-9 years) relapse-free survival or developed tumor relapse within 9–76 months (~1-6 years) we found that the expression of molecules involved in activating signaling of NK cells and in NK cells: target interaction is increased in patients with favorable prognosis.

Conclusions

The parameters identified in this study, together with the prognostic signature previously reported by our group, highlight the cooperation between the innate and adaptive immune components within the tumor microenvironment.
Appendix
Available only for authorised users
Literature
1.
Ascierto ML, Giorgi VD, Liu Q, Bedognetti D, Spivey TL, Murtas D, Uccellini L, Ayotte BD, Stroncek DF, Chouchane L: An immunologic portrait of cancer. J Transl Med. 2011, 9: 146-10.1186/1479-5876-9-146.PubMedCentralCrossRefPubMed
2.
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006, 313: 1960-1964. 10.1126/science.1129139.CrossRefPubMed
3.
Pages F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Marliot F, Bruneval P: In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol. 2009, 27: 5944-5951. 10.1200/JCO.2008.19.6147.CrossRefPubMed
4.
Schumacher K, Haensch W, Roefzaad C, Schlag PM: Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res. 2001, 61: 3932-3936.PubMed
5.
Carretero R, Wang E, Rodriguez AI, Reinboth J, Ascierto ML, Engle AM, Liu H, Camacho FM, Marincola FM, Garrido F, Cabrera T: Regression of melanoma metastases after immunotherapy is associated with activation of antigen presentation and interferon-mediated rejection genes. Int J Cancer. 2012, 131: 387-395. 10.1002/ijc.26471.PubMedCentralCrossRefPubMed
6.
Ascierto ML, Kmieciak M, Idowu MO, Manjili R, Zhao Y, Grimes M, Dumur C, Wang E, Ramakrishnan V, Wang XY: A signature of immune function genes associated with recurrence-free survival in breast cancer patients. Breast Cancer Res Treat. 2012, 131: 871-880. 10.1007/s10549-011-1470-x.PubMedCentralCrossRefPubMed
7.
Shanker A, Verdeil G, Buferne M, Inderberg-Suso EM, Puthier D, Joly F, Nguyen C, Leserman L, Auphan-Anezin N, Schmitt-Verhulst AM: CD8 T cell help for innate antitumor immunity. J Immunol. 2007, 179: 6651-6662.CrossRefPubMed
8.
Wang E, Worschech A, Marincola FM: The immunologic constant of rejection. Trends Immunol. 2008, 29: 256-262. 10.1016/j.it.2008.03.002.CrossRefPubMed
9.
Kmieciak M, Basu D, Payne KK, Toor A, Yacoub A, Wang XY, Smith L, Bear HD, Manjili MH: Activated NKT cells and NK cells render T cells resistant to myeloid-derived suppressor cells and result in an effective adoptive cellular therapy against breast cancer in the FVBN202 transgenic mouse. J Immunol. 2011, 187: 708-717. 10.4049/jimmunol.1100502.PubMedCentralCrossRefPubMed
10.
11.
Vivier E, Ugolini S, Blaise D, Chabannon C, Brossay L: Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol. 2012, 12: 239-252. 10.1038/nri3174.CrossRefPubMed
12.
Ames IH, Garcia AM, John PA, Litty CA, Farrell MA, Tomar RH: Decreased natural cytotoxicity in mice with high incidence of mammary adenocarcinoma. Clin Immunol Immunopathol. 1986, 38: 265-273. 10.1016/0090-1229(86)90144-3.CrossRefPubMed
13.
Cook JL, Lewis AM: Immunological surveillance against DNA-virus-transformed cells: correlations between natural killer cell cytolytic competence and tumor susceptibility of athymic rodents. J Virol. 1987, 61: 2155-2161.PubMedCentralPubMed
14.
Shanker A, Buferne M, Schmitt-Verhulst AM: Cooperative action of CD8 T lymphocytes and natural killer cells controls tumour growth under conditions of restricted T-cell receptor diversity. Immunology. 2010, 129: 41-54. 10.1111/j.1365-2567.2009.03150.x.PubMedCentralCrossRefPubMed
15.
Mamessier E, Sylvain A, Thibult ML, Houvenaeghel G, Jacquemier J, Castellano R, Goncalves A, Andre P, Romagne F, Thibault G: Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J Clin Invest. 2011, 121: 3609-3622. 10.1172/JCI45816.PubMedCentralCrossRefPubMed
16.
Delahaye NF, Rusakiewicz S, Martins I, Menard C, Roux S, Lyonnet L, Paul P, Sarabi M, Chaput N, Semeraro M: Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat Med. 2011, 17: 700-707. 10.1038/nm.2366.CrossRefPubMed
17.
Costello RT, Knoblauch B, Sanchez C, Mercier D, Le Treut T, Sebahoun G: Expression of natural killer cell activating receptors in patients with chronic lymphocytic leukaemia. Immunology. 2012, 135: 151-157. 10.1111/j.1365-2567.2011.03521.x.PubMedCentralCrossRefPubMed
18.
Ascierto ML, Kmieciak M, Idowu M, Grimes M, Dumur C, Wang E, Marincola FM, Bear HD, Manjili MH: Signatures of Immune Function Genes Associated with Recurrence-Free Survival in Breast Cancer Patients. J Immunother. 2010, 33: 881-881.
19.
Marras F, Bozzano F, De Maria A: Involvement of activating NK cell receptors and their modulation in pathogen immunity. J Biomed Biotechnol. 2011, 2011: 152430-PubMedCentralCrossRefPubMed
20.
Moretta A, Biassoni R, Bottino C, Moretta L: Surface receptors delivering opposite signals regulate the function of human NK cells. Semin Immunol. 2000, 12: 129-138. 10.1006/smim.2000.0215.CrossRefPubMed
21.
Worschech A, Chen N, Yu YA, Zhang Q, Pos Z, Weibel S, Raab V, Sabatino M, Monaco A, Liu H: Systemic treatment of xenografts with vaccinia virus GLV-1h68 reveals the immunologic facet of oncolytic therapy. BMC Genomics. 2009, 10: 301-10.1186/1471-2164-10-301.PubMedCentralCrossRefPubMed
22.
Wang E, Miller LD, Ohnmacht GA, Liu ET, Marincola FM: High-fidelity mRNA amplification for gene profiling. Nat Biotechnol. 2000, 18: 457-459. 10.1038/74546.CrossRefPubMed
23.
24.
Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001, 25: 402-408. 10.1006/meth.2001.1262.CrossRefPubMed
25.
Jin P, Zhao Y, Ngalame Y, Panelli MC, Nagorsen D, Monsurro V, Smith K, Hu N, Su H, Taylor PR: Selection and validation of endogenous reference genes using a high throughput approach. BMC Genomics. 2004, 5: 55-10.1186/1471-2164-5-55.PubMedCentralCrossRefPubMed
26.
Simon R, Lam A, Li MC, Ngan M, Menenzes S, Zhao Y: Analysis of gene expression data using BRB-ArrayTools. Cancer Inform. 2007, 3: 11-17.PubMedCentralPubMed
27.
Bair E, Tibshirani R: Semi-supervised methods to predict patient survival from gene expression data. PLoS Biol. 2004, 2: E108-10.1371/journal.pbio.0020108.PubMedCentralCrossRefPubMed
28.
Ringner M, Fredlund E, Hakkinen J, Borg A, Staaf J: GOBO: gene expression-based outcome for breast cancer online. PLoS One. 2011, 6: e17911-10.1371/journal.pone.0017911.PubMedCentralCrossRefPubMed
29.
Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A, Pawitan Y, Hall P, Klaar S, Liu ET, Bergh J: An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci USA. 2005, 102: 13550-13555. 10.1073/pnas.0506230102.PubMedCentralCrossRefPubMed
30.
Pawitan Y, Bjohle J, Amler L, Borg AL, Egyhazi S, Hall P, Han X, Holmberg L, Huang F, Klaar S: Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts. Breast Cancer Res. 2005, 7: R953-964. 10.1186/bcr1325.PubMedCentralCrossRefPubMed
31.
Loi S, Haibe-Kains B, Majjaj S, Lallemand F, Durbecq V, Larsimont D, Gonzalez-Angulo AM, Pusztai L, Symmans WF, Bardelli A: PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. Proc Natl Acad Sci USA. 2010, 107: 10208-10213. 10.1073/pnas.0907011107.PubMedCentralCrossRefPubMed
32.
Desmedt C, Piette F, Loi S, Wang Y, Lallemand F, Haibe-Kains B, Viale G, Delorenzi M, Zhang Y, d’Assignies MS: Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series. Clin Cancer Res. 2007, 13: 3207-3214. 10.1158/1078-0432.CCR-06-2765.CrossRefPubMed
33.
Binsky-Ehrenreich I, Marom A, Sobotta MC, Shvidel L, Berrebi A, Hazan-Halevy I, Kay S, Aloshin A, Sagi I, Goldenberg DM: CD84 is a survival receptor for CLL cells. Oncogene. 2013,  :  -[Epub ahead of print]
34.
Shevach EM: Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009, 30: 636-645. 10.1016/j.immuni.2009.04.010.CrossRefPubMed
35.
Mantovani A, Romero P, Palucka AK, Marincola FM: Tumour immunity: effector response to tumour and role of the microenvironment. Lancet. 2008, 371: 771-783. 10.1016/S0140-6736(08)60241-X.CrossRefPubMed
36.
Spivey TL, Uccellini L, Ascierto ML, Zoppoli G, De Giorgi V, Delogu LG, Engle AM, Thomas JM, Wang E, Marincola FM, Bedognetti D: Gene expression profiling in acute allograft rejection: challenging the immunologic constant of rejection hypothesis. J Transl Med. 2011, 9: 174-10.1186/1479-5876-9-174.PubMedCentralCrossRefPubMed
37.
Shanker A, Marincola FM: Cooperativity of adaptive and innate immunity: implications for cancer therapy. Cancer Immunol Immunother. 2011, 60: 1061-1074. 10.1007/s00262-011-1053-z.PubMedCentralCrossRefPubMed
38.
Coca S, Perez-Piqueras J, Martinez D, Colmenarejo A, Saez MA, Vallejo C, Martos JA, Moreno M: The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer. 1997, 79: 2320-2328. 10.1002/(SICI)1097-0142(19970615)79:12<2320::AID-CNCR5>3.0.CO;2-P.CrossRefPubMed
39.
Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Che X, Iwashige H, Aridome K, Hokita S, Aikou T: Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer. 2000, 88: 577-583. 10.1002/(SICI)1097-0142(20000201)88:3<577::AID-CNCR13>3.0.CO;2-V.CrossRefPubMed
40.
Villegas FR, Coca S, Villarrubia VG, Jimenez R, Chillon MJ, Jareno J, Zuil M, Callol L: Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer. Lung Cancer. 2002, 35: 23-28. 10.1016/S0169-5002(01)00292-6.CrossRefPubMed
41.
Donskov F, von der Maase H: Impact of immune parameters on long-term survival in metastatic renal cell carcinoma. J Clin Oncol. 2006, 24: 1997-2005. 10.1200/JCO.2005.03.9594.CrossRefPubMed
42.
Jochems C, Schlom J: Tumor-infiltrating immune cells and prognosis: the potential link between conventional cancer therapy and immunity. Exp Biol Med (Maywood). 2011, 236: 567-579. 10.1258/ebm.2011.011007.CrossRef
43.
Mamessier E, Sylvain A, Bertucci F, Castellano R, Finetti P, Houvenaeghel G, Charaffe-Jaufret E, Birnbaum D, Moretta A, Olive D: Human Breast Tumor Cells Induce Self-Tolerance Mechanisms to Avoid NKG2D-Mediated and DNAM-Mediated NK Cell Recognition. Cancer Res. 2011, 71: 6621-6632. 10.1158/0008-5472.CAN-11-0792.CrossRefPubMed
44.
45.
Fuchs A, Cella M, Giurisato E, Shaw AS, Colonna M: Cutting edge: CD96 (tactile) promotes NK cell-target cell adhesion by interacting with the poliovirus receptor (CD155). J Immunol. 2004, 172: 3994-3998.CrossRefPubMed
46.
Chan CJ, Andrews DM, McLaughlin NM, Yagita H, Gilfillan S, Colonna M, Smyth MJ: DNAM-1/CD155 interactions promote cytokine and NK cell-mediated suppression of poorly immunogenic melanoma metastases. J Immunol. 2010, 184: 902-911. 10.4049/jimmunol.0903225.CrossRefPubMed
47.
Mace EM, Zhang J, Siminovitch KA, Takei F: Elucidation of the integrin LFA-1-mediated signaling pathway of actin polarization in natural killer cells. Blood. 2010, 116: 1272-1279. 10.1182/blood-2009-12-261487.CrossRefPubMed
48.
Gilfillan S, Chan CJ, Cella M, Haynes NM, Rapaport AS, Boles KS, Andrews DM, Smyth MJ, Colonna M: DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors. J Exp Med. 2008, 205: 2965-2973. 10.1084/jem.20081752.PubMedCentralCrossRefPubMed
49.
Moretta L, Bottino C, Pende D, Castriconi R, Mingari MC, Moretta A: Surface NK receptors and their ligands on tumor cells. Semin Immunol. 2006, 18: 151-158. 10.1016/j.smim.2006.03.002.CrossRefPubMed
50.
Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari MC, Biassoni R, Moretta L: Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol. 2001, 19: 197-223. 10.1146/annurev.immunol.19.1.197.CrossRefPubMed
51.
Merlo A, Casalini P, Carcangiu ML, Malventano C, Triulzi T, Menard S, Tagliabue E, Balsari A: FOXP3 expression and overall survival in breast cancer. J Clin Oncol. 2009, 27: 1746-1752. 10.1200/JCO.2008.17.9036.CrossRefPubMed
52.
Correale P, Rotundo MS, Del Vecchio MT, Remondo C, Migali C, Ginanneschi C, Tsang KY, Licchetta A, Mannucci S, Loiacono L: Regulatory (FoxP3+) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy. J Immunother. 2010, 33: 435-441. 10.1097/CJI.0b013e3181d32f01.CrossRefPubMed
53.
Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pages F, Galon J: Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 2011, 71: 1263-1271. 10.1158/0008-5472.CAN-10-2907.CrossRefPubMed
54.
Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B: gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011, 364: 2119-2127. 10.1056/NEJMoa1012863.PubMedCentralCrossRefPubMed
55.
Le DT, Ladle BH, Lee T, Weiss V, Yao X, Leubner A, Armstrong TD, Jaffee EM: CD8 Foxp3 tumor infiltrating lymphocytes accumulate in the context of an effective anti-tumor response. Int J Cancer. 2011, 129: 636-647. 10.1002/ijc.25693.PubMedCentralCrossRefPubMed
56.
Karanikas V, Speletas M, Zamanakou M, Kalala F, Loules G, Kerenidi T, Barda AK, Gourgoulianis KI, Germenis AE: Foxp3 expression in human cancer cells. J Transl Med. 2008, 6: 19-10.1186/1479-5876-6-19.PubMedCentralCrossRefPubMed
57.
Wang L, Liu R, Li W, Chen C, Katoh H, Chen GY, McNally B, Lin L, Zhou P, Zuo T: Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate. Cancer Cell. 2009, 16: 336-346. 10.1016/j.ccr.2009.08.016.PubMedCentralCrossRefPubMed
Metadata
Title
Molecular signatures mostly associated with NK cells are predictive of relapse free survival in breast cancer patients
Authors
Maria Libera Ascierto
Michael O Idowu
Yingdong Zhao
Hanif Khalak
Kyle K Payne
Xiang-Yang Wang
Catherine I Dumur
Davide Bedognetti
Sara Tomei
Paolo A Ascierto
Anil Shanker
Harry D Bear
Ena Wang
Francesco M Marincola
Andrea De Maria
Masoud H Manjili
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2013
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/1479-5876-11-145

Other articles of this Issue 1/2013

Journal of Translational Medicine 1/2013 Go to the issue

Research

Dynamically expressed microRNA-15b modulates the activities of CD8+ T lymphocytes in mice with Lewis lung carcinoma

Research

Adipose stromal cells primed with hypoxia and inflammation enhance cardiomyocyte proliferation rate in vitro through STAT3 and Erk1/2

Research

Effects of hepatocyte nuclear factor-1A and -4A on pancreatic stone protein/regenerating protein and C-reactive protein gene expression: implications for maturity-onset diabetes of the young

Research

Race and gender variation in response to evoked inflammation

Research

Prognostic assessment of hypoxia and metabolic markers in cervical cancer using automated digital image analysis of immunohistochemistry

Commentary

T and NK cells: two sides of tumor immunoevasion
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits