Gastrointestinal tumor immunology

Our studies aim to provide knowledge to design and improve immunotherapies for Hepatocellular Carcinoma, Cholangiocarcinoma, and Colorectal Cancer. Our studies which aim to identify therapeutic targets to overcome the immunosuppressive tumor micro-environment focus on the regulation of cytotoxic T cells and helper T cells by co-inhibitory and co-stimulatory immune checkpoint pathways and regulatory T cells in human tumors. Most studies are performed using blood or tissues from patients.

Liver transplantation immunology
As a follow-up of the former research focus of the research group, we are still involved in studies aiming to find biomarkers that can identify liver transplant patients who are immunologically tolerant to their graft and can be safely withdrawn from immunosuppressive therapy.

1. van Beek AA, Zhou G, Doukas M, Boor PPC, Noordam L, Mancham S, Campos Carrascosa L, van der Heide-Mulder M, Polak WG, IJzermans JNM, Pan Q, Heirman C, Mahne A, Bucktrout SL, Bruno MJ, Sprengers D, Kwekkeboom J. GITR-ligation enhances functionality of tumor-infiltrating T cells in hepatocellular carcinoma. Int. J. Cancer 2019; 2019 Aug 15; 145(4): 1111–1124. doi: 10.1002/ijc.32181 [Epub ahead of print].
2. Zhou G, Noordam L, Sprengers D, Doukas M, Boor PPC, van Beek AA, Erkens R, Mancham S, Grunhagen D, Menon AG, Lange JF, Burger P, Brandt A, Galjart B, Verhoef C, Kwekkeboom J, Bruno MJ. Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer. Oncoimmunology 2018;7(7): e1448332.
3. Zhou G, Sprengers D, Boor PPC, Doukas M, Schutz H, Mancham S, Pedroza-Gonzalez A, Polak WG, de Jonge J, Gaspersz M, Dong H, Thielemans K, Pan Q, IJzermans JNM, Bruno MJ, Kwekkeboom J. Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas. 
   Gastroenterology 2017;153(4): 1107-1119 e1110.
4. Sideras K, Biermann K, Verheij J, Takkenberg BR, Mancham S, Hansen BE, Schutz HM, de Man RA, Sprengers D, Buschow SI, Verseput MC, Boor PP, Pan Q, van Gulik TM, Terkivatan T, IJzermans JN, Beuers UH, Sleijfer S, Bruno MJ, Kwekkeboom J. PD-L1, Galectin-9 and CD8(+) tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma. 
   Oncoimmunology 2017;6(2): e1273309.
5. Shi XL, Mancham S, Hansen BE, de Knegt RJ, de Jonge J, van der Laan LJ, Rivadeneira F, Metselaar HJ, Kwekkeboom J. Counter-regulation of rejection activity against human liver grafts by donor PD-L1 and recipient PD-1 interaction.J Hepatol 2016;64(6): 1274-1282.
6. Pedroza-Gonzalez A, Zhou G, Vargas-Mendez E, Boor PP, Mancham S, Verhoef C, Polak WG, Grunhagen D, Pan Q, Janssen H, Garcia-Romo GS, Biermann K, Tjwa ET, JN IJzermans, Kwekkeboom J, Sprengers D. Tumor-infiltrating plasmacytoid dendritic cells promote immunosuppression by Tr1 cells in human liver tumors. Oncoimmunology 2015;4(6): e1008355.
7. Pedroza-Gonzalez A, Zhou G, Singh SP, Boor PP, Pan Q, Grunhagen D, de Jonge J, Tran TK, Verhoef C, JN IJ, Janssen H, Biermann K, Kwekkeboom J, Sprengers D. GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cells ex vivo. Oncoimmunology 2015;4(12): e1051297.
8. Shi XL, de Mare-Bredemeijer EL, Tapirdamaz O, Hansen BE, van Gent R, van Campenhout MJ, Mancham S, Litjens NH, Betjes MG, van der Eijk AA, Xia Q, van der Laan LJ, de Jonge J, Metselaar HJ, Kwekkeboom J. CMV Primary Infection Is Associated With Donor-Specific T Cell Hyporesponsiveness and Fewer Late Acute Rejections After Liver Transplantation. 
   Am J Transplant 2015;15(9): 2431-2442.
9. de Mare-Bredemeijer EL, Shi XL, Mancham S, van Gent R, van der Heide-Mulder M, de Boer R, Heemskerk MH, de Jonge J, van der Laan LJ, Metselaar HJ, Kwekkeboom J. Cytomegalovirus-Induced Expression of CD244 after Liver Transplantation Is Associated with CD8+ T Cell Hyporesponsiveness to Alloantigen. J Immunol 2015;195(4): 1838-1848 
   
   

We collaborate closely with gastroenterologists of our department (Dr. D. Sprengers and Dr. R.J. de Knegt), and with oncological surgeons of Erasmus MC (Prof. Dr. J.N.M. IJzermans and Prof. Dr. C. Verhoef) and of other medical centers. In addition, we collaborate with other research groups within our laboratory and of other departments within Erasmus MC.

Jaap Kwekkeboom, PhD (Principal Investigator)
Guoying Zhou, MD, PhD (postdoc)
Lucia Campos Carrascosa, PhD (postdoc)
Lisanne Noordam, MD (PhD-student)
Aafke Duizendstra (PhD-student)
Zhouhong Ge (PhD-student)
Bastiaan Rakké, MD (PhD-student)
Patrick Boor, PhD (research technician)
Shanta Mancham (research technician)
Valeska de Ruiter (research technician)