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

Journal of Translational Medicine

Masoud H Manjili^1,10  Andrea De Maria⁴  Francesco M Marincola²  Ena Wang¹  Harry D Bear³  Anil Shanker⁵  Paolo A Ascierto⁷  Sara Tomei⁶  Davide Bedognetti¹  Catherine I Dumur^1,11  Xiang-Yang Wang⁸  Kyle K Payne^1,10  Hanif Khalak⁶  Yingdong Zhao⁹  Michael O Idowu^1,11  Maria Libera Ascierto⁴ 

[1] Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and FOCIS Center of Excellence, National Institutes of Health, Bethesda, MD, USA;Chief Research Officer Sidra Medical and Research Centre, Doha, Qatar;Department of Surgery, Virginia Commonwealth University, Massey Cancer Centre, Richmond, VA, USA;Department of Health Sciences and Centre of Excellence for Biomedical Research University of Genoa, Genoa, Italy;Laboratory of Lymphocyte Function, Department of Biochemistry & Cancer Biology, School of Medicine, Meharry Medical College, Vanderbilt-Ingram Cancer Centre, Vanderbilt University, Nashville, TN, USA;Weill Cornell Medical College (WCMC), Doha, Qatar;Unit of Medical Oncology and Innovative Therapy, Istituto Nazionale Tumori Fondazione “G. Pascale”, Naples, Italy;Department of Human Genetics, Virginia Commonwealth University, Massey Cancer Centre, Richmond, VA, USA;Biometric research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA;Department of Microbiology & Immunology, Virginia Commonwealth University, Massey Cancer Centre, Richmond, VA, USA;Department of Pathology, Virginia Commonwealth University, Massey Cancer Centre, Richmond, VA, USA

关键词: Tumour microenvironment;    Tumour relapse;    NK cells;    Innate immunity;    Molecular markers;    Breast cancer prognosis;   

Others  :  827416
DOI  :  10.1186/1479-5876-11-145

 received in 2013-03-01, accepted in 2013-06-04,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Ascierto et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Ascierto ML, Giorgi VD, Liu Q, Bedognetti D, Spivey TL, Murtas D, Uccellini L, Ayotte BD, Stroncek DF, Chouchane L, et al.: An immunologic portrait of cancer. J Transl Med 2011, 9:146. BioMed Central Full Text
• [2]Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, et al.: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006, 313:1960-1964.
• [3]Pages F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Marliot F, Bruneval P, et al.: In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 2009, 27:5944-5951.
• [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.
• [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.
• [6]Ascierto ML, Kmieciak M, Idowu MO, Manjili R, Zhao Y, Grimes M, Dumur C, Wang E, Ramakrishnan V, Wang XY, et al.: A signature of immune function genes associated with recurrence-free survival in breast cancer patients. Breast Cancer Res Treat 2012, 131:871-880.
• [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.
• [8]Wang E, Worschech A, Marincola FM: The immunologic constant of rejection. Trends Immunol 2008, 29:256-262.
• [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]Moretta L: NK cell-mediated immune response against cancer. Surg Oncol 2007, 16(Suppl 1):S3-5.
• [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.
• [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.
• [13]Cook JL, Lewis AM Jr: 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.
• [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.
• [15]Mamessier E, Sylvain A, Thibult ML, Houvenaeghel G, Jacquemier J, Castellano R, Goncalves A, Andre P, Romagne F, Thibault G, et al.: Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J Clin Invest 2011, 121:3609-3622.
• [16]Delahaye NF, Rusakiewicz S, Martins I, Menard C, Roux S, Lyonnet L, Paul P, Sarabi M, Chaput N, Semeraro M, et al.: Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat Med 2011, 17:700-707.
• [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.
• [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.
• [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.
• [21]Worschech A, Chen N, Yu YA, Zhang Q, Pos Z, Weibel S, Raab V, Sabatino M, Monaco A, Liu H, et al.: Systemic treatment of xenografts with vaccinia virus GLV-1h68 reveals the immunologic facet of oncolytic therapy. BMC Genomics 2009, 10:301. BioMed Central Full Text
• [22]Wang E, Miller LD, Ohnmacht GA, Liu ET, Marincola FM: High-fidelity mRNA amplification for gene profiling. Nat Biotechnol 2000, 18:457-459.
• [23]Wang E: RNA amplification for successful gene profiling analysis. J Transl Med 2005, 3:28. BioMed Central Full Text
• [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.
• [25]Jin P, Zhao Y, Ngalame Y, Panelli MC, Nagorsen D, Monsurro V, Smith K, Hu N, Su H, Taylor PR, et al.: Selection and validation of endogenous reference genes using a high throughput approach. BMC Genomics 2004, 5:55. BioMed Central Full Text
• [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.
• [27]Bair E, Tibshirani R: Semi-supervised methods to predict patient survival from gene expression data. PLoS Biol 2004, 2:E108.
• [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.
• [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.
• [30]Pawitan Y, Bjohle J, Amler L, Borg AL, Egyhazi S, Hall P, Han X, Holmberg L, Huang F, Klaar S, et al.: 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. BioMed Central Full Text
• [31]Loi S, Haibe-Kains B, Majjaj S, Lallemand F, Durbecq V, Larsimont D, Gonzalez-Angulo AM, Pusztai L, Symmans WF, Bardelli A, et al.: 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.
• [32]Desmedt C, Piette F, Loi S, Wang Y, Lallemand F, Haibe-Kains B, Viale G, Delorenzi M, Zhang Y, d’Assignies MS, et al.: 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.
• [33]Binsky-Ehrenreich I, Marom A, Sobotta MC, Shvidel L, Berrebi A, Hazan-Halevy I, Kay S, Aloshin A, Sagi I, Goldenberg DM, et al.: 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.
• [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.
• [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. BioMed Central Full Text
• [37]Shanker A, Marincola FM: Cooperativity of adaptive and innate immunity: implications for cancer therapy. Cancer Immunol Immunother 2011, 60:1061-1074.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [44]Malhotra A, Shanker A: NK cells: immune cross-talk and therapeutic implications. Immunotherapy 2011, 3:1143-1166.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [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.
• [52]Correale P, Rotundo MS, Del Vecchio MT, Remondo C, Migali C, Ginanneschi C, Tsang KY, Licchetta A, Mannucci S, Loiacono L, et al.: 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.
• [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.
• [54]Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B, et al.: gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 2011, 364:2119-2127.
• [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.
• [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. BioMed Central Full Text
• [57]Wang L, Liu R, Li W, Chen C, Katoh H, Chen GY, McNally B, Lin L, Zhou P, Zuo T, et al.: Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate. Cancer Cell 2009, 16:336-346.