Decoding the tumor microenvironment : a B-cell and macrophage perspective
Author: Boura, Vanessa F
Date: 2019-05-24
Location: CMB Lecture Hall, Berzelius väg 21, Karolinska Institutet, Solna
Time: 09.30
Department: Inst för mikrobiologi, tumör- och cellbiologi / Dept of Microbiology, Tumor and Cell Biology
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Thesis (1.242Mb)
Abstract
The immune system plays a role in many different functions in our body, and disease is no exception. Cancer is one of the biggest challenges of the twenty first century and vast efforts have been made to understand this disease. Since the 1900s, we have evidence based that the immune system participates in cancer progression, but it was only some decades ago that we started to investigate it extensively. Currently, we know that the tumor microenvironment is infiltrated by different immune cells and depending on space and time they can participate in tumor initiation, promotion, progression and metastasis. Moreover, it has been shown that certain immune cell can influence tumor resistance to therapy. So far, most of the studies have been directed towards understanding tumor infiltrating T cells. However, in this thesis I focused on the interplay between different immune cells including B cells, T cells, Natural killer cells, macrophages and the tumor cells. Further from this research, we found potential predictive biomarkers associated with the checkpoint therapies, such as anti-CTLA-4, anti-PD-1 and anti-PD-L1.
This thesis can be divided into two major studies investigating two immune cell types infiltrating the tumor, B cells (Paper I and II) and macrophages (Paper III and IV). More specifically, Paper I touches upon the role of B cells infiltrating two types of tumors, melanoma and breast cancer, studied in mouse models. Here, we could detect the presence of a heterogeneous B cell population that could be further divided by its surface CD5 expression. These subpopulations were phenotypically and functionally distinct. In particular, CD5+ TIBs were found to have an activated phenotype and were able to secrete proinflammatory cytokines, which were induced by the tumor milieu. Additionally, we identified a similar B cell subpopulation in human breast cancer highlighting the importance of this finding. Paper II focused on the B cell responses towards melanoma when treated with immune checkpoint therapies anti-PD-1 or anti-PD-L1. This study showed an augmented IgG response against the tumor mice treated with checkpoint antibodies. More importantly, it revealed significant differences in IgG subclasses depending on the checkpoint treatment given.
In the second part of the thesis, paper III identifies MARCO, a scavenger receptor, as a novel marker for immunosuppressive TAMs subset present in three different mouse models, namely melanoma, mammary carcinoma and colon cancer. Monoclonal antibody against MARCO was found to successfully decrease the tumor growth and metastasis, while re-polarizing this subpopulation of TAMs to have an anti-tumor phenotype. Moreover, we could observe an enhanced effect of anti-CTLA-4 treatment when combined with anti-MARCO. Finally, MARCO proved to be expressed in human metastatic melanoma and in an aggressive breast cancer subtype. Thus, targeting MARCO could potentially be a combinatory treatment for these cancer types. Paper IV further provides evidence on MARCO expression in adistinct subset of immunosuppressive TAMs, but now in human non-small cell lung cancer. Moreover, this study uncovered the strategical localization of MARCO positive macrophages at the tumor-stroma border. This creates an immunosuppressive barrier that could be potentially targeted with anti-MARCO.
In summary, this thesis contributes to our overall understanding of the tumor microenvironment, specifically of B cells and macrophages. It gives us new possible targets and approaches for cancer therapy as well as potential predictive biomarkers.
This thesis can be divided into two major studies investigating two immune cell types infiltrating the tumor, B cells (Paper I and II) and macrophages (Paper III and IV). More specifically, Paper I touches upon the role of B cells infiltrating two types of tumors, melanoma and breast cancer, studied in mouse models. Here, we could detect the presence of a heterogeneous B cell population that could be further divided by its surface CD5 expression. These subpopulations were phenotypically and functionally distinct. In particular, CD5+ TIBs were found to have an activated phenotype and were able to secrete proinflammatory cytokines, which were induced by the tumor milieu. Additionally, we identified a similar B cell subpopulation in human breast cancer highlighting the importance of this finding. Paper II focused on the B cell responses towards melanoma when treated with immune checkpoint therapies anti-PD-1 or anti-PD-L1. This study showed an augmented IgG response against the tumor mice treated with checkpoint antibodies. More importantly, it revealed significant differences in IgG subclasses depending on the checkpoint treatment given.
In the second part of the thesis, paper III identifies MARCO, a scavenger receptor, as a novel marker for immunosuppressive TAMs subset present in three different mouse models, namely melanoma, mammary carcinoma and colon cancer. Monoclonal antibody against MARCO was found to successfully decrease the tumor growth and metastasis, while re-polarizing this subpopulation of TAMs to have an anti-tumor phenotype. Moreover, we could observe an enhanced effect of anti-CTLA-4 treatment when combined with anti-MARCO. Finally, MARCO proved to be expressed in human metastatic melanoma and in an aggressive breast cancer subtype. Thus, targeting MARCO could potentially be a combinatory treatment for these cancer types. Paper IV further provides evidence on MARCO expression in adistinct subset of immunosuppressive TAMs, but now in human non-small cell lung cancer. Moreover, this study uncovered the strategical localization of MARCO positive macrophages at the tumor-stroma border. This creates an immunosuppressive barrier that could be potentially targeted with anti-MARCO.
In summary, this thesis contributes to our overall understanding of the tumor microenvironment, specifically of B cells and macrophages. It gives us new possible targets and approaches for cancer therapy as well as potential predictive biomarkers.
List of papers:
I. Boura, V.F., Sohn, S., Hoekstra, E., Sarhan, D., Pedersen, G., Erikson, E., McGaha, T., Karlsson Hedestam, G. B., Karlsson, M. C. I. The tumor microenvironment induces innate cytokine producing B cells. [Manuscript]
II. Boura, V.F., Sohn, S., Hallgren, Å., Pico de Coaña, Y., Kämpe, O., Kiessling, R, Karlsson, M. C. I. B cell responses to checkpoint therapy in melanoma. [Manuscript]
III. Georgoudaki, A.-M., Prokopec, K. E., Boura, V. F., Hellqvist, E., Sohn, S., Östling, J., Dahan R., Harris, R. A., Rantalainen, M., Klevebring, D., Sund, M., Brage, S. E., Fuxe, J., Rohlny, C., Li, F., Ravetch, J. V., Karlsson, M. C. I. (2016). Reprogramming Tumor-Associated Macrophages by Antibody Targeting Inhibits Cancer Progression and Metastasis. Cell Reports. 15(9), 2000–2011.
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IV. La Fleur, L., Boura, V. F., Alexeyenko, A., Berglund, A., Pontén, V., Mattsson, J. S. M., Djureinovic, D., Persson, J., Brunnström, H., Isaksson, J., Brandén, E., Koyi, H., Micke, P., Karlsson, M. C. I. and Botling, J. (2018). Expression of scavenger receptor MARCO defines a targetable tumor-associated macrophage subset in non-small cell lung cancer. International Journal of Cancer. 143(7), pp. 1741–1752.
Fulltext (DOI)
Pubmed
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I. Boura, V.F., Sohn, S., Hoekstra, E., Sarhan, D., Pedersen, G., Erikson, E., McGaha, T., Karlsson Hedestam, G. B., Karlsson, M. C. I. The tumor microenvironment induces innate cytokine producing B cells. [Manuscript]
II. Boura, V.F., Sohn, S., Hallgren, Å., Pico de Coaña, Y., Kämpe, O., Kiessling, R, Karlsson, M. C. I. B cell responses to checkpoint therapy in melanoma. [Manuscript]
III. Georgoudaki, A.-M., Prokopec, K. E., Boura, V. F., Hellqvist, E., Sohn, S., Östling, J., Dahan R., Harris, R. A., Rantalainen, M., Klevebring, D., Sund, M., Brage, S. E., Fuxe, J., Rohlny, C., Li, F., Ravetch, J. V., Karlsson, M. C. I. (2016). Reprogramming Tumor-Associated Macrophages by Antibody Targeting Inhibits Cancer Progression and Metastasis. Cell Reports. 15(9), 2000–2011.
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Pubmed
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IV. La Fleur, L., Boura, V. F., Alexeyenko, A., Berglund, A., Pontén, V., Mattsson, J. S. M., Djureinovic, D., Persson, J., Brunnström, H., Isaksson, J., Brandén, E., Koyi, H., Micke, P., Karlsson, M. C. I. and Botling, J. (2018). Expression of scavenger receptor MARCO defines a targetable tumor-associated macrophage subset in non-small cell lung cancer. International Journal of Cancer. 143(7), pp. 1741–1752.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Karlsson, Mikael
Co-supervisor: Wilhelm, Margareta; Fuxe, Jonas
Issue date: 2019-05-02
Rights:
Publication year: 2019
ISBN: 978-91-7831-457-7
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