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Steven A Rosenberg - One of the best experts on this subject based on the ideXlab platform.
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recombinant fowlpox viruses encoding the anchor modified gp100 Melanoma Antigen can generate antitumor immune responses in patients with metastatic Melanoma
Clinical Cancer Research, 2003Co-Authors: Steven A Rosenberg, Nicholas P. Restifo, Suzanne L Topalian, James Chihhsin Yang, Douglas J Schwartzentruber, Richard M Sherry, John R Wunderlich, Claudia A Seipp, Linda Rogersfreezer, Kathleen E MortonAbstract:Purpose: The purpose of this study was to evaluate the immunological responses and therapeutic effectiveness of immunization with fowlpox vaccines encoding the gp100 Melanoma Antigen in patients with metastatic Melanoma. Experimental Design: In three consecutive clinical trials, patients were immunized with recombinant fowlpox viruses encoding three different forms of the Melanoma/melanocyte-associated Antigen gp100: ( a ) the native, full-length gp100 molecule; ( b ) the gp100 molecule with two amino acids modified to increase binding to HLA-A*0201 molecules; and ( c ) a “minigene” construct encoding a single, modified epitope gp100:209–217(210M) targeted to the endoplasmic reticulum. The immunogenicity of these constructs was studied using peripheral blood mononuclear cells to measure epitope-specific release of IFN-γ. Results: Reactivity against gp100 was not seen in any patient before receiving fowlpox immunization. Whereas just one of seven patients developed reactivity after receiving fowlpox encoding native gp100, 10 of 14 patients who received fowlpox encoding the anchor modified full-length gp100 exhibited reactivity against the native gp100 molecule, and 12 of 16 patients were successfully immunized after inoculation with the modified minigene construct (p2 = 0.02). There was no difference in the latter group between those randomized to vaccination by i.v. or i.m. routes. There was one partial cancer regression in the group of 46 patients receiving virus in the absence of interleukin (IL)-2. Once patients showed evidence of progressive disease, they were eligible for “cross-over” treatment to IL-2 alone or with the fowlpox virus. None of the 13 patients receiving the full-length or modified full-length forms of gp100 responded when receiving IL-2, whereas 6 of 12 patients who received the fowlpox containing the minigene construct and then received IL-2 showed objective cancer regressions, including three patients with complete regression. Conclusions: These data underscore the importance of modifying anchor residues of nonmutated self-Antigen peptides to generate cellular immune responses after immunization and support the further investigation of recombinant fowlpox viruses encoding modified epitopes administered in combination with IL-2.
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immune selection after Antigen specific immunotherapy of Melanoma
Surgery, 1999Co-Authors: Adam I Riker, Steven A Rosenberg, Janice N Cormier, Monica C Panelli, Udai S Kammula, Ena Wang, Andrea Abati, Patricia Fetsch, Seth M Steinberg, Francesco M MarincolaAbstract:Abstract Background: Melanoma Antigen (MA)–specific vaccination strongly enhances antitumor reactivity in vivo and is capable of producing strong cytotoxic T lymphocyte responses in vitro. Furthermore, specific human leukocyte Antigen–restricted T cell activation is hypothesized to occur in response to peptide-based immunotherapy, which may lead to the preferential killing of tumor cells bearing the relevant MA. The development of Melanoma Antigen-loss variants may subsequently occur in vivo. Methods: Analysis of 532 Melanoma lesions from 204 patients was performed on fine-needle aspiration biopsy specimens. Lesions were graded for the expression of the MAs gp100 and MART-1 with use of immunocytochemistry. A total of 351 Melanoma lesions were divided into cohorts on the basis of the treatment received. The pretreatment group (n = 175) consisted of lesions obtained before any form of gp100 immunotherapy, with the posttreatment group (n = 176) consisting of lesions obtained after vaccination with a modified gp100 epitope, gp209-2M +/– interleukin 2 (IL-2). Results: The percentage of lesions not expressing the gp100 Antigen is greater than the percentage not expressing MART-1 (26% vs 14%). The frequency of lesions with high expression (>75%) of gp100 significantly decreased with therapy (47% vs 34%) and conversely negative lesions increased (18% vs 29%). Treatment of lesions with peptide alone (no IL-2) revealed a significant decrease in gp100 expression (47% vs 32%), enhanced with the addition of IL-2 to therapy (47% vs 35%). The expression of MART-1 remained essentially unchanged unless IL-2 was added (54% vs 54%, MART-1 peptide alone, 54% vs 43%, MART-1 peptide + IL-2). Of 94 patients (181 lesions) assessed for gp100 expression before treatment, 10 patients responded to therapy. Pretreatment lesions in responding patients expressed some level of gp100 in all cases compared with 27% of nonresponding lesions, which were negative for gp100 expression. Conclusions: This study indirectly demonstrates that vaccination with an MA-derived peptide can result in immune selection in vivo. Furthermore, it provides strong immunologic evidence for the specificity of MA vaccines and to the relevance of MA expression in predicting the response to vaccination. (Surgery 1999;126:112-20.)
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cloning genes encoding mhc class ii restricted Antigens mutated cdc27 as a tumor Antigen
Science, 1999Co-Authors: Rongfu Wang, Suzanne L Topalian, Xiang Wang, Alicia C Atwood, Steven A RosenbergAbstract:In an effort to identify tumor-specific Antigens recognized by CD4+ T cells, an approach was developed that allows the screening of an invariant chain–complementary DNA fusion library in a genetically engineered cell line expressing the essential components of the major histocompatibility complex (MHC) class II processing and presentation pathway. This led to the identification of a mutated form of human CDC27, which gave rise to an HLA-DR4–restricted Melanoma Antigen. A mutated form of triosephosphate isomerase, isolated by a biochemical method, was also identified as an HLA-DR1–restricted Antigen. Thus, this approach may be generally applicable to the identification of Antigens recognized by CD4+ T cells, which could aid the development of strategies for the treatment of patients with cancer, autoimmune diseases, or infectious diseases.
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biochemical identification of a mutated human Melanoma Antigen recognized by cd4 t cells
Journal of Experimental Medicine, 1999Co-Authors: Rembert Pieper, Steven A Rosenberg, Robert E Christian, Monica Gonzales, Michael I Nishimura, Gaorav P Gupta, Robert E Settlage, Jeffrey Shabanowitz, Donald F Hunt, Suzanne L TopalianAbstract:CD4+ T cells play a critical role in generating and maintaining immune responses against pathogens and alloAntigens, and evidence suggests an important role for them in antitumor immunity as well. Although major histocompatibility complex class II–restricted human CD4+ T cells with specific antitumor reactivities have been described, no standard method exists for cloning the recognized tumor-associated Antigen (Ag). In this study, biochemical protein purification methods were used in conjunction with novel mass spectrometry sequencing techniques and molecular cloning to isolate a unique Melanoma Ag recognized by a CD4+ tumor-infiltrating lymphocyte (TIL) line. The HLA-DRβ1*0101–restricted Ag was determined to be a mutated glycolytic enzyme, triosephosphate isomerase (TPI). A C to T mutation identified by cDNA sequencing caused a Thr to Ile conversion in TPI, which could be detected in a tryptic digest of tumor-derived TPI by mass spectrometry. The Thr to Ile conversion created a neoepitope whose T cell stimulatory activity was enhanced at least 5 logs compared with the wild-type peptide. Analysis of T cell recognition of serially truncated peptides suggested that the mutated amino acid residue was a T cell receptor contact. Defining human tumor Ag recognized by T helper cells may provide important clues to designing more effective immunotherapies for cancer.
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identification of a shared hla a 0201 restricted t cell epitope from the Melanoma Antigen tyrosinase related protein 2 trp2
Cancer Research, 1998Co-Authors: Maria R Parkhurst, Steven A Rosenberg, Ellen B Fitzgerald, Scott Southwood, Alessandro Sette, Yutaka KawakamiAbstract:Abstract Tyrosinase-related protein 2 (TRP2) is a melanosomal enzyme expressed in most mammalian melanocytes and Melanomas. This protein has been identified as a Melanoma Antigen recognized by tumor reactive CTLs derived from tumor infiltrating lymphocytes in the context of HLA-A31 and HLA-A33. The frequencies of these HLA-A alleles among Melanoma patients in the United States is low (∼6% for HLA-A31 and ∼2% for HLA-A33) compared with that of HLA-A*0201 (∼46%). Therefore, to extend significantly the use of TRP2-based immunotherapies for the treatment of patients with Melanoma, we searched for new HLA-A*0201-restricted epitopes from this protein by screening TRP2-derived peptides for the induction of Melanoma-reactive CTL. Fifty-one peptides were selected from TRP2 based on a permissive HLA-A*0201 binding motif, and the 21 peptides with the highest experimentally determined binding affinities were used to stimulate peripheral blood lymphocytes from HLA-A*0201+ Melanoma patients in vitro. One peptide, TRP2(180–188) (SVYDFFVWL), induced CTLs from three of four patients that specifically recognized peptide-pulsed T2 cells, COS-7 cells expressing HLA-A*0201 and TRP2, and HLA-A2+ TRP2+ Melanomas. TRP2(180–188) is identical to a previously identified TRP2 epitope recognized by murine Melanoma-reactive CTLs in the context of H-2Kb. These results suggest that TRP2 may be useful for the development of murine tumor immunotherapy models and for the treatment of Melanoma patients who are diverse in HLA expression.
Regine Gatje - One of the best experts on this subject based on the ideXlab platform.
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Melanoma Antigen family a identified by the bimodality index defines a subset of triple negative breast cancers as candidates for immune response augmentation
European Journal of Cancer, 2012Co-Authors: Thomas Karn, Lajos Pusztai, E Ruckhaberle, Cornelia Liedtke, Volkmar Muller, Marcus Schmidt, Dirk Metzler, Jing Wang, Kevin R Coombes, Regine GatjeAbstract:Abstract Background Molecular markers displaying bimodal expression distribution can reveal distinct disease subsets and may serve as prognostic or predictive markers or represent therapeutic targets. Oestrogen (ER) and human epidermal growth factor receptor 2 (HER2) receptors are strongly bimodally expressed genes in breast cancer. Material and methods We applied a novel method to identify bimodally expressed genes in 394 triple negative breast cancers (TNBC). We identified 133 bimodally expressed probe sets (128 unique genes), 69 of these correlated to previously reported metagenes that define molecular subtypes within TNBC including basal-like, molecular-apocrine, claudin-low and immune cell rich subgroups but 64 probe sets showed no correlation with these features. Results The single most prominent functional group among these uncorrelated genes was the X chromosome derived Cancer/Testis Antigens (CT-X) including Melanoma Antigen family A (MAGE-A) and Cancer/Testis Antigens (CTAG). High expression of CT-X genes correlated with worse survival in multivariate analysis (HR 2.02, 95% CI 1.27–3.20; P = 0.003). The only other significant variable was lymph node status. The poor prognosis of patients with high MAGE-A expression was ameliorated by the concomitant high expression of immune cell metagenes (HR 1.87, 95% CI 0.96–3.64; P = 0.060), whereas the same immune metagene had lesser prognostic value in TNBC with low MAGE-A expression. Conclusions MAGE-A Antigen defines a very aggressive subgroup of TNBC; particularly in the absence of immune infiltration in the tumour microenvironment. These observations suggest a therapeutic hypothesis; TNBC with MAGE-A expression may benefit the most from further augmentation of the immune response. Novel immune stimulatory drugs such as (anti-cytotoxic T-lymphocyte Antigen-4 CTLA-4) directed therapies provide a realistic opportunity to directly test this hypothesis in the clinic.
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Melanoma Antigen family a identified by the bimodality index defines a subset of triple negative breast cancers as candidates for immune response augmentation
European Journal of Cancer, 2012Co-Authors: Thomas Karn, Lajos Pusztai, E Ruckhaberle, Cornelia Liedtke, Volkmar Muller, Marcus Schmidt, Dirk Metzler, Jing Wang, Kevin R Coombes, Regine GatjeAbstract:BACKGROUND: Molecular markers displaying bimodal expression distribution can reveal distinct disease subsets and may serve as prognostic or predictive markers or represent therapeutic targets. Oestrogen (ER) and human epidermal growth factor receptor 2 (HER2) receptors are strongly bimodally expressed genes in breast cancer. MATERIAL AND METHODS: We applied a novel method to identify bimodally expressed genes in 394 triple negative breast cancers (TNBC). We identified 133 bimodally expressed probe sets (128 unique genes), 69 of these correlated to previously reported metagenes that define molecular subtypes within TNBC including basal-like, molecular-apocrine, claudin-low and immune cell rich subgroups but 64 probe sets showed no correlation with these features. RESULTS: The single most prominent functional group among these uncorrelated genes was the X chromosome derived Cancer/Testis Antigens (CT-X) including Melanoma Antigen family A (MAGE-A) and Cancer/Testis Antigens (CTAG). High expression of CT-X genes correlated with worse survival in multivariate analysis (HR 2.02, 95% CI 1.27-3.20; P=0.003). The only other significant variable was lymph node status. The poor prognosis of patients with high MAGE-A expression was ameliorated by the concomitant high expression of immune cell metagenes (HR 1.87, 95% CI 0.96-3.64; P=0.060), whereas the same immune metagene had lesser prognostic value in TNBC with low MAGE-A expression. CONCLUSIONS: MAGE-A Antigen defines a very aggressive subgroup of TNBC; particularly in the absence of immune infiltration in the tumour microenvironment. These observations suggest a therapeutic hypothesis; TNBC with MAGE-A expression may benefit the most from further augmentation of the immune response. Novel immune stimulatory drugs such as (anti-cytotoxic T-lymphocyte Antigen-4 CTLA-4) directed therapies provide a realistic opportunity to directly test this hypothesis in the clinic.
Yutaka Kawakami - One of the best experts on this subject based on the ideXlab platform.
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identification of a shared hla a 0201 restricted t cell epitope from the Melanoma Antigen tyrosinase related protein 2 trp2
Cancer Research, 1998Co-Authors: Maria R Parkhurst, Steven A Rosenberg, Ellen B Fitzgerald, Scott Southwood, Alessandro Sette, Yutaka KawakamiAbstract:Abstract Tyrosinase-related protein 2 (TRP2) is a melanosomal enzyme expressed in most mammalian melanocytes and Melanomas. This protein has been identified as a Melanoma Antigen recognized by tumor reactive CTLs derived from tumor infiltrating lymphocytes in the context of HLA-A31 and HLA-A33. The frequencies of these HLA-A alleles among Melanoma patients in the United States is low (∼6% for HLA-A31 and ∼2% for HLA-A33) compared with that of HLA-A*0201 (∼46%). Therefore, to extend significantly the use of TRP2-based immunotherapies for the treatment of patients with Melanoma, we searched for new HLA-A*0201-restricted epitopes from this protein by screening TRP2-derived peptides for the induction of Melanoma-reactive CTL. Fifty-one peptides were selected from TRP2 based on a permissive HLA-A*0201 binding motif, and the 21 peptides with the highest experimentally determined binding affinities were used to stimulate peripheral blood lymphocytes from HLA-A*0201+ Melanoma patients in vitro. One peptide, TRP2(180–188) (SVYDFFVWL), induced CTLs from three of four patients that specifically recognized peptide-pulsed T2 cells, COS-7 cells expressing HLA-A*0201 and TRP2, and HLA-A2+ TRP2+ Melanomas. TRP2(180–188) is identical to a previously identified TRP2 epitope recognized by murine Melanoma-reactive CTLs in the context of H-2Kb. These results suggest that TRP2 may be useful for the development of murine tumor immunotherapy models and for the treatment of Melanoma patients who are diverse in HLA expression.
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identification of a human Melanoma Antigen recognized by tumor infiltrating lymphocytes associated with in vivo tumor rejection
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Yutaka Kawakami, Siona Eliyahu, Cynthia H Delgado, Paul F Robbins, Toru Miki, Kazuyasu Sakaguchi, Ettore Appella, John R Yannelli, Gosse Jan Adema, Steven A RosenbergAbstract:Abstract The cultured T-cell line TIL1200, established from the tumor-infiltrating lymphocytes (TILs) of a patient with advanced metastatic Melanoma, recognized an Antigen on most HLA-A2+ Melanomas and on all HLA-A2+ cultured neonatal melanocytes in an HLA-A2 restricted manner but not on other types of tissues or cell lines tested. A cDNA encoding an Antigen recognized by TIL1200 was isolated by screening an HLA-A2+ breast cancer cell line transfected with an expression cDNA library prepared from an HLA-A2+ Melanoma cell line. The nucleotide and amino acid sequences of this cDNA were almost identical to the genes encoding glycoprotein gp100 or Pmel17 previously registered in the GenBank. Expression of this gene was restricted to Melanoma and melanocyte cell lines and retina but was not expressed on other fresh or cultured normal tissues or other types of tumor tested. The cell line transfected with this cDNA also expressed Antigen recognized by the Melanoma-specific antibody HMB45 that bound to gp100. A synthetic 10-amino acid peptide derived from gp100 was recognized by TIL1200 in the context of HLA-A2.1. Since the administration of TIL1200 plus interleukin 2 resulted in regression of metastatic cancer in the autologous patient, gp100 is a possible tumor rejection Antigen and may be useful for the development of immunotherapies for patients with Melanoma.
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cloning of the gene coding for a shared human Melanoma Antigen recognized by autologous t cells infiltrating into tumor
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Yutaka Kawakami, Siona Eliyahu, Cynthia H Delgado, Paul F Robbins, Licia Rivoltini, Suzanne L Topalian, Toru Miki, Steven A RosenbergAbstract:Abstract By cDNA expression cloning we have isolated a gene encoding a shared human Melanoma Antigen recognized by HLA-A2 restricted autologous and allogenic tumor-infiltrating lymphocytes (TILs) from patients with metastatic Melanoma. By using both transient and stable expression systems, transfection of this gene into non-Antigen-expressing HLA-A2+ cell lines resulted in recognition by the Antigen-specific TILs. The sequence of this cDNA revealed a previously undescribed putative transmembrane protein whose expression was restricted to Melanoma and melanocyte cell lines and human retina but no other fresh or cultured normal tissues tested or other tumor histologies. Thus, we have identified a gene encoding a melanocyte lineage-specific protein (MART-1; Melanoma Antigen recognized by T cells 1) that is a widely shared Melanoma Antigen recognized by the T lymphocytes of patients with established malignancy. Identification of this gene opens possibilities for the development of immunotherapies for patients with Melanoma.
Peter Cresswell - One of the best experts on this subject based on the ideXlab platform.
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cytosolic processing governs tap independent presentation of a critical Melanoma Antigen
Journal of Immunology, 2018Co-Authors: Peter Cresswell, Nathalie Vigneron, Violette Ferrari, Benoit Van Den Eynde, Ralf M LeonhardtAbstract:Cancer immunotherapy has been flourishing in recent years with remarkable clinical success. But as more patients are treated, a shadow is emerging that has haunted other cancer therapies: tumors develop resistance. Resistance is often caused by defects in the MHC class I Ag presentation pathway critical for CD8 T cell–mediated tumor clearance. TAP and tapasin, both key players in the pathway, are frequently downregulated in human cancers, correlating with poor patient survival. Reduced dependence on these factors may promote vaccine efficiency by limiting immune evasion. In this study, we demonstrate that PMEL 209–217 , a promising phase 3 trial–tested antiMelanoma vaccine candidate, is robustly presented by various TAP- and/or tapasin-deficient cell lines. This striking characteristic may underlie its potency as a vaccine. Surprisingly, cytosolic proteasomes generate the peptide even for TAP-independent presentation, whereas tripeptidyl peptidase 2 (TPP2) efficiently degrades the epitope. Consequently, inhibiting TPP2 substantially boosts PMEL 209–217 presentation, suggesting a possible strategy to improve the therapeutic efficacy of the vaccine.
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gilt accelerates autoimmunity to the Melanoma Antigen tyrosinase related protein 1
Journal of Immunology, 2010Co-Authors: Matthew Rausch, Nicholas P. Restifo, Kari R Irvine, Paul A Antony, Peter Cresswell, Taraszka K HastingsAbstract:Melanocyte differentiation Ags, including tyrosinase-related protein (TRP) 1, are relevant to both autoimmune skin depigmentation (vitiligo) and tumor immunity, because they are expressed by both benign melanocytes and many malignant Melanomas. Melanoma patients generate CD4+ T cells that specifically recognize these proteins. TRP1 contains internal disulfide bonds and is presented by MHC class II molecules. γ-IFN–inducible lysosomal thiol reductase (GILT) facilitates the generation of class II-binding peptides by the endocytic reduction of protein disulfide bonds. We show in this study that GILT is required for efficient MHC class II-restricted processing of a TRP1 epitope in vitro and accelerates the onset of vitiligo in TRP1-specific TCR transgenic mice. The presence of GILT confers a small increase in the percentage of autoreactive T cells with an effector memory phenotype that may contribute to earlier disease onset. The onset of vitiligo is associated with a greater increase in the percentage of autoreactive T cells with an effector memory phenotype. Given that many self and tumor Ags have disulfide bonds and are presented on MHC class II, GILT is likely to be important in the pathogenesis of other CD4+ T cell-mediated autoimmune diseases and for the development of effective cancer immunotherapy.
Thomas Karn - One of the best experts on this subject based on the ideXlab platform.
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Melanoma Antigen family a identified by the bimodality index defines a subset of triple negative breast cancers as candidates for immune response augmentation
European Journal of Cancer, 2012Co-Authors: Thomas Karn, Lajos Pusztai, E Ruckhaberle, Cornelia Liedtke, Volkmar Muller, Marcus Schmidt, Dirk Metzler, Jing Wang, Kevin R Coombes, Regine GatjeAbstract:Abstract Background Molecular markers displaying bimodal expression distribution can reveal distinct disease subsets and may serve as prognostic or predictive markers or represent therapeutic targets. Oestrogen (ER) and human epidermal growth factor receptor 2 (HER2) receptors are strongly bimodally expressed genes in breast cancer. Material and methods We applied a novel method to identify bimodally expressed genes in 394 triple negative breast cancers (TNBC). We identified 133 bimodally expressed probe sets (128 unique genes), 69 of these correlated to previously reported metagenes that define molecular subtypes within TNBC including basal-like, molecular-apocrine, claudin-low and immune cell rich subgroups but 64 probe sets showed no correlation with these features. Results The single most prominent functional group among these uncorrelated genes was the X chromosome derived Cancer/Testis Antigens (CT-X) including Melanoma Antigen family A (MAGE-A) and Cancer/Testis Antigens (CTAG). High expression of CT-X genes correlated with worse survival in multivariate analysis (HR 2.02, 95% CI 1.27–3.20; P = 0.003). The only other significant variable was lymph node status. The poor prognosis of patients with high MAGE-A expression was ameliorated by the concomitant high expression of immune cell metagenes (HR 1.87, 95% CI 0.96–3.64; P = 0.060), whereas the same immune metagene had lesser prognostic value in TNBC with low MAGE-A expression. Conclusions MAGE-A Antigen defines a very aggressive subgroup of TNBC; particularly in the absence of immune infiltration in the tumour microenvironment. These observations suggest a therapeutic hypothesis; TNBC with MAGE-A expression may benefit the most from further augmentation of the immune response. Novel immune stimulatory drugs such as (anti-cytotoxic T-lymphocyte Antigen-4 CTLA-4) directed therapies provide a realistic opportunity to directly test this hypothesis in the clinic.
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Melanoma Antigen family a identified by the bimodality index defines a subset of triple negative breast cancers as candidates for immune response augmentation
European Journal of Cancer, 2012Co-Authors: Thomas Karn, Lajos Pusztai, E Ruckhaberle, Cornelia Liedtke, Volkmar Muller, Marcus Schmidt, Dirk Metzler, Jing Wang, Kevin R Coombes, Regine GatjeAbstract:BACKGROUND: Molecular markers displaying bimodal expression distribution can reveal distinct disease subsets and may serve as prognostic or predictive markers or represent therapeutic targets. Oestrogen (ER) and human epidermal growth factor receptor 2 (HER2) receptors are strongly bimodally expressed genes in breast cancer. MATERIAL AND METHODS: We applied a novel method to identify bimodally expressed genes in 394 triple negative breast cancers (TNBC). We identified 133 bimodally expressed probe sets (128 unique genes), 69 of these correlated to previously reported metagenes that define molecular subtypes within TNBC including basal-like, molecular-apocrine, claudin-low and immune cell rich subgroups but 64 probe sets showed no correlation with these features. RESULTS: The single most prominent functional group among these uncorrelated genes was the X chromosome derived Cancer/Testis Antigens (CT-X) including Melanoma Antigen family A (MAGE-A) and Cancer/Testis Antigens (CTAG). High expression of CT-X genes correlated with worse survival in multivariate analysis (HR 2.02, 95% CI 1.27-3.20; P=0.003). The only other significant variable was lymph node status. The poor prognosis of patients with high MAGE-A expression was ameliorated by the concomitant high expression of immune cell metagenes (HR 1.87, 95% CI 0.96-3.64; P=0.060), whereas the same immune metagene had lesser prognostic value in TNBC with low MAGE-A expression. CONCLUSIONS: MAGE-A Antigen defines a very aggressive subgroup of TNBC; particularly in the absence of immune infiltration in the tumour microenvironment. These observations suggest a therapeutic hypothesis; TNBC with MAGE-A expression may benefit the most from further augmentation of the immune response. Novel immune stimulatory drugs such as (anti-cytotoxic T-lymphocyte Antigen-4 CTLA-4) directed therapies provide a realistic opportunity to directly test this hypothesis in the clinic.