This information is current as of March 4, 2015.
Response to Comment on ''Multiplex B Cell Characterization in Blood, Lymph Nodes, and Tumors from Patients with Malignancies'' Per Marits, Ali A. Zirakzadeh, Amir Sherif and Ola Winqvist J Immunol 2013; 191:4471-4472; ; doi: 10.4049/jimmunol.1390053 http://www.jimmunol.org/content/191/9/4471
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This article cites 6 articles, 3 of which you can access for free at: http://www.jimmunol.org/content/191/9/4471.full#ref-list-1 Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscriptions Submit copyright permission requests at: http://www.aai.org/ji/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/cgi/alerts/etoc
The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 9650 Rockville Pike, Bethesda, MD 20814-3994. Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606.
Downloaded from http://www.jimmunol.org/ at University of Michigan on March 4, 2015
References
The
Letters to the Editor Comment on “Multiplex B Cell Characterization in Blood, Lymph Nodes, and Tumors from Patients with Malignancies”
I
Immunology
depletion in mycosis fungoides, demonstrate that targeting of regulatory B cells seems to be a promising therapeutic concept and that balance between regulatory and terminally differentiated B cells might be of importance (6, 7). Therefore, a detailed understanding of the composition of the B cell infiltrate in tumors will be necessary for the application of B cell–targeted therapeutic interventions for the immunotherapy of malignant diseases. Alexander Shimabukuro-Vornhagen,* Hans Anton Schlo¨ßer,*,† Dirk Ludger Stippel,† Sebastian Theurich,* and Michael von Bergwelt-Baildon* *Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital Cologne, 50937 Ko¨ln, Germany; and †Department of Surgery, University Hospital Cologne, 50937 Ko¨ln, Germany Address correspondence and reprint requests to Alexander Shimabukuro-Vornhagen, Cologne Interventional Immunology, Department I of Internal Medicine and Department of Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Ko¨ln, Germany. E-mail address: [email protected]
References 1. Nelson, B. H. 2010. CD201 B cells: the other tumor-infiltrating lymphocytes. J. Immunol. 185: 4977–4982. 2. Zirakzadeh, A. A., P. Marits, A. Sherif, and O. Winqvist. 2013. Multiplex B cell characterization in blood, lymph nodes, and tumors from patients with malignancies. J. Immunol. 190: 5847–5855. 3. Carpenter, E. L., R. Mick, A. J. Rech, G. L. Beatty, T. A. Colligon, M. R. Rosenfeld, D. E. Kaplan, K.-M. Chang, S. M. Domchek, P. A. Kanetsky, et al. 2009. Collapse of the CD271 B-cell compartment associated with systemic plasmacytosis in patients with advanced melanoma and other cancers. Clin. Cancer Res. 15: 4277–4287. 4. Schmidt, M., B. Hellwig, S. Hammad, A. Othman, M. Lohr, Z. Chen, D. Boehm, S. Gebhard, I. Petry, A. Lebrecht, et al. 2012. A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin k C as a compatible prognostic marker in human solid tumors. Clin. Cancer Res. 18: 2695–2703. 5. Blair, P. A., L. Y. Noren˜a, F. Flores-Borja, D. J. Rawlings, D. A. Isenberg, M. R. Ehrenstein, and C. Mauri. 2010. CD19(1)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. Immunity 32: 129–140. 6. Theurich, S., M. Schlaak, H. Steguweit, L. Heukamp, K. Wennhold, P. Kurschat, A. Rabenhorst, K. Hartmann, H. Schloesser, A. Shimabukuro-Vornhagen, et al. Targeting tumor infiltrating B cells in cutaneous T-cell lymphoma. J. Clin. Oncol. In press. 7. Wejksza, K., C. Lee-Chang, M. Bodogai, J. Bonzo, F. J. Gonzalez, E. Lehrmann, K. Becker, and A. Biragyn. 2013. Cancer-produced metabolites of 5-lipoxygenase induce tumor-evoked regulatory B cells via peroxisome proliferator-activated receptor a. J. Immunol. 190: 2575–2584. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1390052
FIGURE 1. Analysis of B cells in the peripheral blood of patients with esophageal cancer (n 5 22). (A) The percentage of plasmablasts and CD24high CD38high B cells is significantly increased in the peripheral blood. (B) The B cell infiltrate differed in the histologic subtypes. Adenocarcinomas (n 5 16) of the esophagus had a comparable percentage of plasmablasts but a higher proportion of CD24high CD38high B cells than squamous cell carcinoma (n 5 6) of the esophagus. Bars represent means 6 SEM. *p , 0.05.
Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00
Response to Comment on “Multiplex B Cell Characterization in Blood, Lymph Nodes, and Tumors from Patients with Malignancies”
W
e appreciate the comments made by Dr. Shimabukuro-Vornhagen and colleagues on our investigation of tumor-associated B cells in human subjects. Indeed, a complementary investigation of regulatory B cells (Bregs) would be of interest in cancer patients.
Downloaded from http://www.jimmunol.org/ at University of Michigan on March 4, 2015
n recent years it has been increasingly appreciated that B cells constitute a significant part of the immune infiltrate of solid tumors (1). In their interesting paper, Zirakzadeh et al. demonstrate that solid tumors and metastatic lymph nodes are enriched for terminally differentiated B cells, i.e., memory B cells and plasmablasts (2). They furthermore provide evidence that these tumor-associated B cells presumably represent tumor Ag-specific B lymphocytes, which have undergone clonal expansion. Our analysis of patients with esophageal cancer confirms the finding of a plasmacytosis in the peripheral blood (Fig. 1A). The accumulation of plasma cells seems to be a general phenomenon in many tumor entities, and is associated with a better prognosis (3, 4). In addition, we found an increase in CD24highCD38high B cells (Fig. 1A), a subset with regulatory capacity (5). Interestingly, while both adenocarcinoma and squamous cell carcinoma of the esophagus had similar percentages of plasmablasts, adenocarcinomas had a higher proportion of CD24highCD38high B cells (Fig. 1B). Because they solely used the Freiburg classification, Zirakzadeh et al. omit regulatory B cell subsets from their analyses. However, recent publications, including our study of local B cell–
Journal of
4472
Per Marits,* Ali A. Zirakzadeh,* Amir Sherif,† and Ola Winqvist* *Department of Medicine, Unit of Translational Immunology, Karolinska Institutet, 171 76 Stockholm, Sweden; and †Department of Surgical and Perioperative Sciences, Urology and Andrology, Umea˚ University Hospital, 901 85 Umea˚, Sweden Address correspondence and reprint requests to Prof. Ola Winqvist, Unit of Translational Immunology, Department of Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden. E-mail address: [email protected]
References 1. Blair, P. A., L. Y. Noren˜a, F. Flores-Borja, D. J. Rawlings, D. A. Isenberg, M. R. Ehrenstein, and C. Mauri. 2010. CD19(1)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. Immunity 32: 129–140. 2. Olkhanud, P. B., B. Damdinsuren, M. Bodogai, R. E. Gress, R. Sen, K. Wejksza, E. Malchinkhuu, R. P. Wersto, and A. Biragyn. 2011. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4⁺ T cells to T-regulatory cells. Cancer Res. 71: 3505–3515. 3. Warnatz, K., and M. Schlesier. 2008. Flowcytometric phenotyping of common variable immunodeficiency. Cytometry B Clin. Cytom. 74: 261–271. 4. Kuzmina, Z., H. T. Greinix, R. Weigl, U. Ko¨rmo¨czi, A. Rottal, S. Frantal, S. Eder, and W. F. Pickl. 2011. Significant differences in B-cell subpopulations characterize patients with chronic graft-versus-host disease-associated dysgammaglobulinemia. Blood 117: 2265–2274. 5. Iwata, Y., T. Matsushita, M. Horikawa, D. J. Dilillo, K. Yanaba, G. M. Venturi, P. M. Szabolcs, S. H. Bernstein, C. M. Magro, A. D. Williams, et al. 2011. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood 117: 530–541. 6. Kessel, A., T. Haj, R. Peri, A. Snir, D. Melamed, E. Sabo, and E. Toubi. 2012. Human CD19(1)CD25(high) B regulatory cells suppress proliferation of CD4(1) T cells and enhance Foxp3 and CTLA-4 expression in T-regulatory cells. Autoimmun. Rev. 11: 670–677. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1390053
Downloaded from http://www.jimmunol.org/ at University of Michigan on March 4, 2015
Most of the data regarding Bregs in humans has been collected from patients with autoimmunity (1), whereas information on this subset in human cancer is scarce. Even in rodents, the possible involvement of Bregs in tumor immune escape has been poorly investigated. Interestingly, a recent report of tumor-induced Bregs in breast cancer describes a TGF-b–producing subset of B cells, with a surface phenotype distinct from that reported in the context of autoimmunity (2). Our choice of the Freiburg panel for flow cytometric analysis of tumor-associated B cells was primarily motivated by its widespread use and that it has been thoroughly validated in a number of clinical conditions (3, 4). We feel that the choice of surface markers to identify Bregs would be significantly more speculative. Most authors have identified Bregs by their ability to produce IL-10 and subsequently defined their phenotype. Apart from the CD24highCD38high B cell subset advocated by Shimabukuro-Vornhagen and others (1), staining for CD24high CD271 (5) or the combination CD25highCD27highCD86high CD1dhigh (6) to enrich for regulatory B cells has been suggested. However, as indicated by the study by Olkhanud et al. (2), tumor-associated Bregs may be distinct from those found in healthy subjects and systemic lupus erythematosus patients. Therefore, Breg investigations in malignancy would call for accompanying functional analyses of cytokine profile and capacity to suppress T cell proliferation. We look forward to reading the forthcoming publications from Dr. ShimabukuroVornhagen et al. on this subject.
LETTERS TO THE EDITOR
Response to Comment on ''Multiplex B Cell Characterization in Blood, Lymph Nodes, and Tumors from Patients with Malignancies'' Per Marits, Ali A. Zirakzadeh, Amir Sherif and Ola Winqvist J Immunol 2013; 191:4471-4472; ; doi: 10.4049/jimmunol.1390053 http://www.jimmunol.org/content/191/9/4471
Subscriptions Permissions Email Alerts
This article cites 6 articles, 3 of which you can access for free at: http://www.jimmunol.org/content/191/9/4471.full#ref-list-1 Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscriptions Submit copyright permission requests at: http://www.aai.org/ji/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/cgi/alerts/etoc
The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 9650 Rockville Pike, Bethesda, MD 20814-3994. Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606.
Downloaded from http://www.jimmunol.org/ at University of Michigan on March 4, 2015
References
The
Letters to the Editor Comment on “Multiplex B Cell Characterization in Blood, Lymph Nodes, and Tumors from Patients with Malignancies”
I
Immunology
depletion in mycosis fungoides, demonstrate that targeting of regulatory B cells seems to be a promising therapeutic concept and that balance between regulatory and terminally differentiated B cells might be of importance (6, 7). Therefore, a detailed understanding of the composition of the B cell infiltrate in tumors will be necessary for the application of B cell–targeted therapeutic interventions for the immunotherapy of malignant diseases. Alexander Shimabukuro-Vornhagen,* Hans Anton Schlo¨ßer,*,† Dirk Ludger Stippel,† Sebastian Theurich,* and Michael von Bergwelt-Baildon* *Cologne Interventional Immunology, Department I of Internal Medicine, University Hospital Cologne, 50937 Ko¨ln, Germany; and †Department of Surgery, University Hospital Cologne, 50937 Ko¨ln, Germany Address correspondence and reprint requests to Alexander Shimabukuro-Vornhagen, Cologne Interventional Immunology, Department I of Internal Medicine and Department of Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Ko¨ln, Germany. E-mail address: [email protected]
References 1. Nelson, B. H. 2010. CD201 B cells: the other tumor-infiltrating lymphocytes. J. Immunol. 185: 4977–4982. 2. Zirakzadeh, A. A., P. Marits, A. Sherif, and O. Winqvist. 2013. Multiplex B cell characterization in blood, lymph nodes, and tumors from patients with malignancies. J. Immunol. 190: 5847–5855. 3. Carpenter, E. L., R. Mick, A. J. Rech, G. L. Beatty, T. A. Colligon, M. R. Rosenfeld, D. E. Kaplan, K.-M. Chang, S. M. Domchek, P. A. Kanetsky, et al. 2009. Collapse of the CD271 B-cell compartment associated with systemic plasmacytosis in patients with advanced melanoma and other cancers. Clin. Cancer Res. 15: 4277–4287. 4. Schmidt, M., B. Hellwig, S. Hammad, A. Othman, M. Lohr, Z. Chen, D. Boehm, S. Gebhard, I. Petry, A. Lebrecht, et al. 2012. A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin k C as a compatible prognostic marker in human solid tumors. Clin. Cancer Res. 18: 2695–2703. 5. Blair, P. A., L. Y. Noren˜a, F. Flores-Borja, D. J. Rawlings, D. A. Isenberg, M. R. Ehrenstein, and C. Mauri. 2010. CD19(1)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. Immunity 32: 129–140. 6. Theurich, S., M. Schlaak, H. Steguweit, L. Heukamp, K. Wennhold, P. Kurschat, A. Rabenhorst, K. Hartmann, H. Schloesser, A. Shimabukuro-Vornhagen, et al. Targeting tumor infiltrating B cells in cutaneous T-cell lymphoma. J. Clin. Oncol. In press. 7. Wejksza, K., C. Lee-Chang, M. Bodogai, J. Bonzo, F. J. Gonzalez, E. Lehrmann, K. Becker, and A. Biragyn. 2013. Cancer-produced metabolites of 5-lipoxygenase induce tumor-evoked regulatory B cells via peroxisome proliferator-activated receptor a. J. Immunol. 190: 2575–2584. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1390052
FIGURE 1. Analysis of B cells in the peripheral blood of patients with esophageal cancer (n 5 22). (A) The percentage of plasmablasts and CD24high CD38high B cells is significantly increased in the peripheral blood. (B) The B cell infiltrate differed in the histologic subtypes. Adenocarcinomas (n 5 16) of the esophagus had a comparable percentage of plasmablasts but a higher proportion of CD24high CD38high B cells than squamous cell carcinoma (n 5 6) of the esophagus. Bars represent means 6 SEM. *p , 0.05.
Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00
Response to Comment on “Multiplex B Cell Characterization in Blood, Lymph Nodes, and Tumors from Patients with Malignancies”
W
e appreciate the comments made by Dr. Shimabukuro-Vornhagen and colleagues on our investigation of tumor-associated B cells in human subjects. Indeed, a complementary investigation of regulatory B cells (Bregs) would be of interest in cancer patients.
Downloaded from http://www.jimmunol.org/ at University of Michigan on March 4, 2015
n recent years it has been increasingly appreciated that B cells constitute a significant part of the immune infiltrate of solid tumors (1). In their interesting paper, Zirakzadeh et al. demonstrate that solid tumors and metastatic lymph nodes are enriched for terminally differentiated B cells, i.e., memory B cells and plasmablasts (2). They furthermore provide evidence that these tumor-associated B cells presumably represent tumor Ag-specific B lymphocytes, which have undergone clonal expansion. Our analysis of patients with esophageal cancer confirms the finding of a plasmacytosis in the peripheral blood (Fig. 1A). The accumulation of plasma cells seems to be a general phenomenon in many tumor entities, and is associated with a better prognosis (3, 4). In addition, we found an increase in CD24highCD38high B cells (Fig. 1A), a subset with regulatory capacity (5). Interestingly, while both adenocarcinoma and squamous cell carcinoma of the esophagus had similar percentages of plasmablasts, adenocarcinomas had a higher proportion of CD24highCD38high B cells (Fig. 1B). Because they solely used the Freiburg classification, Zirakzadeh et al. omit regulatory B cell subsets from their analyses. However, recent publications, including our study of local B cell–
Journal of
4472
Per Marits,* Ali A. Zirakzadeh,* Amir Sherif,† and Ola Winqvist* *Department of Medicine, Unit of Translational Immunology, Karolinska Institutet, 171 76 Stockholm, Sweden; and †Department of Surgical and Perioperative Sciences, Urology and Andrology, Umea˚ University Hospital, 901 85 Umea˚, Sweden Address correspondence and reprint requests to Prof. Ola Winqvist, Unit of Translational Immunology, Department of Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden. E-mail address: [email protected]
References 1. Blair, P. A., L. Y. Noren˜a, F. Flores-Borja, D. J. Rawlings, D. A. Isenberg, M. R. Ehrenstein, and C. Mauri. 2010. CD19(1)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. Immunity 32: 129–140. 2. Olkhanud, P. B., B. Damdinsuren, M. Bodogai, R. E. Gress, R. Sen, K. Wejksza, E. Malchinkhuu, R. P. Wersto, and A. Biragyn. 2011. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4⁺ T cells to T-regulatory cells. Cancer Res. 71: 3505–3515. 3. Warnatz, K., and M. Schlesier. 2008. Flowcytometric phenotyping of common variable immunodeficiency. Cytometry B Clin. Cytom. 74: 261–271. 4. Kuzmina, Z., H. T. Greinix, R. Weigl, U. Ko¨rmo¨czi, A. Rottal, S. Frantal, S. Eder, and W. F. Pickl. 2011. Significant differences in B-cell subpopulations characterize patients with chronic graft-versus-host disease-associated dysgammaglobulinemia. Blood 117: 2265–2274. 5. Iwata, Y., T. Matsushita, M. Horikawa, D. J. Dilillo, K. Yanaba, G. M. Venturi, P. M. Szabolcs, S. H. Bernstein, C. M. Magro, A. D. Williams, et al. 2011. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood 117: 530–541. 6. Kessel, A., T. Haj, R. Peri, A. Snir, D. Melamed, E. Sabo, and E. Toubi. 2012. Human CD19(1)CD25(high) B regulatory cells suppress proliferation of CD4(1) T cells and enhance Foxp3 and CTLA-4 expression in T-regulatory cells. Autoimmun. Rev. 11: 670–677. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1390053
Downloaded from http://www.jimmunol.org/ at University of Michigan on March 4, 2015
Most of the data regarding Bregs in humans has been collected from patients with autoimmunity (1), whereas information on this subset in human cancer is scarce. Even in rodents, the possible involvement of Bregs in tumor immune escape has been poorly investigated. Interestingly, a recent report of tumor-induced Bregs in breast cancer describes a TGF-b–producing subset of B cells, with a surface phenotype distinct from that reported in the context of autoimmunity (2). Our choice of the Freiburg panel for flow cytometric analysis of tumor-associated B cells was primarily motivated by its widespread use and that it has been thoroughly validated in a number of clinical conditions (3, 4). We feel that the choice of surface markers to identify Bregs would be significantly more speculative. Most authors have identified Bregs by their ability to produce IL-10 and subsequently defined their phenotype. Apart from the CD24highCD38high B cell subset advocated by Shimabukuro-Vornhagen and others (1), staining for CD24high CD271 (5) or the combination CD25highCD27highCD86high CD1dhigh (6) to enrich for regulatory B cells has been suggested. However, as indicated by the study by Olkhanud et al. (2), tumor-associated Bregs may be distinct from those found in healthy subjects and systemic lupus erythematosus patients. Therefore, Breg investigations in malignancy would call for accompanying functional analyses of cytokine profile and capacity to suppress T cell proliferation. We look forward to reading the forthcoming publications from Dr. ShimabukuroVornhagen et al. on this subject.
LETTERS TO THE EDITOR
