The breakthrough therapeutic efficacy of immune checkpoint inhibitors underlines the central role of the immune system in cancer. Infiltration of lymphocytes has been shown to either exhibit an inhibitory or enhancing effect on tumor growth. Especially the role of tumor-infiltrating B cells is complex. B cells serve many immunological functions including antigen-presentation, antibody-secretion, direct toxicity, cytokine secretion, but also immune inhibition. Whether B cells promote or inhibit tumor growth seems to depend on a number of variables such as tumor type, stage and the dominating B cell subset. However, a high density of T and B cells in the tumor microenviroment is correlated with increased patient survival in several types of cancer. For many years, it was assumed that an adaptive anti-tumor immune response is elicited not in the tumor itself, but in secondary lymphoid organs (SLO). However recently, increasing evidence suggests that anti-tumor immune reactions may also be generated in the tumor microenvironment in so called tertiary lymphoid structures (TLS). These TLS display an overall structure similar to that of SLOs with predominant B-cell rich areas surrounded by specialized blood vessels, i.e. high endothelial venules, and T-cell rich areas that contain clusters of T cells and mature dendritic cells. However, the role of cellular components on TLS formation or the function of lymphocytes in TLS of cancer patients is still not well understood.
Specific aim 1: Deciphering the role of B cells in anti-tumor immune responses of TLS in murine pancreatic adenocarcinoma.
Specific aim 2: Identification of soluble and cellular factors influencing TLS-formation in the tumor microenvironment of two pancreatic adenocarcinoma models.
Specific aim 3: Defining TLS in human pancreatic cancer
TLS reflect an ongoing anti-tumor immune response and thus are of great interest as biomarkers for immune interventions. Furthermore, induction of TLS and transfer of single cellular TLS components both merit detailed analysis concerning their potential role as therapeutic approaches in advanced pancreatic cancer.
Kruger, S., Ilmer, M., Kobold, S., Cadilha, B.L., Endres, S., Ormanns, S., Schuebbe, G., Renz, B.W., D'Haese, J.G., Schloesser, H., Heinemann, V., Subklewe, M., Boeck, S., Werner, J., and von Bergwelt-Baildon, M. (2019). Advances in cancer immunotherapy 2019 - latest trends. J Exp Clin Cancer Res 38, 268.
Lechner, A., Schlosser, H.A., Thelen, M., Wennhold, K., Rothschild, S.I., Gilles, R., Quaas, A., Siefer, O.G., Huebbers, C.U., Cukuroglu, E., Goke, J., Hillmer, A., Gathof, B., Meyer, M.F., Klussmann, J.P., Shimabukuro-Vornhagen, A., Theurich, S., Beutner, D., and von Bergwelt-Baildon, M. (2019). Tumor-associated B cells and humoral immune response in head and neck squamous cell carcinoma. Oncoimmunology 8, 1535293.
Mellinghoff, S.C., von Bergwelt-Baildon, M., Schosser, H.A., and Cornely, O.A. (2019). A novel approach to candidemia? The potential role of checkpoint inhibition. Med Mycol 57, 151-4.
Schlosser, H.A., Thelen, M., Lechner, A., Wennhold, K., Garcia-Marquez, M.A., Rothschild, S.I., Staib, E., Zander, T., Beutner, D., Gathof, B., Gilles, R., Cukuroglu, E., Goke, J., Shimabukuro-Vornhagen, A., Drebber, U., Quaas, A., Bruns, C.J., Holscher, A.H., and Von Bergwelt-Baildon, M.S. (2019). B cells in esophago-gastric adenocarcinoma are highly differentiated, organize in tertiary lymphoid structures and produce tumor-specific antibodies. Oncoimmunology 8, e1512458.
Wennhold, K., Shimabukuro-Vornhagen, A., and von Bergwelt-Baildon, M. (2019). B Cell-Based Cancer Immunotherapy. Transfus Med Hemother 46, 36-46.
Meder L, Schuldt P, Thelen M, Schmitt A, Dietlein F, Klein S, Borchmann S, Wennhold K, Vlasic I, Oberbeck S, Riedel R, Florin A, Golfmann K, Schlosser HA, Odenthal M, Buttner R, Wolf J, Hallek M, Herling M, von Bergwelt-Baildon M, Reinhardt HC, and Ullrich RT (2018). Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer. Cancer Res 10.1158/0008-5472.CAN-17-2176.
Schlosser HA, Thelen M, Lechner A, Wennhold K, Garcia-Marquez MA, Rothschild SI, Staib E, Zander T, Beutner D, Gathof B, Gilles R, Cukuroglu E, Goke J, Shimabukuro-Vornhagen A, Drebber U, Quaas A, Bruns CJ, Holscher AH, and Von Bergwelt-Baildon MS (2019). B cells in esophago-gastric adenocarcinoma are highly differentiated, organize in tertiary lymphoid structures and produce tumor-specific antibodies. Oncoimmunology 8, e1512458.
Shimabukuro-Vornhagen A, Godel P, Subklewe M, Stemmler HJ, Schlosser HA, Schlaak M, Kochanek M, Boll B, and von Bergwelt-Baildon MS (2018). Cytokine release syndrome. J Immunother Cancer 6, 56.
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Dept. I of Internal Medicine / RG location - Building 16
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