SP 5

Therapeutic potential of T cell responses against tumor initiating cell-associated antigens in CRC

The prognosis of colorectal carcinoma (CRC) patients is dependent on the establishment of distant metastases, which  according to the recent findings of KFO SP2 arise from a small population of  long term tumor initiating cells (LT-TIC), located in the primary tumor tissue, in the bone marrow and in metastatic lesions.

The extent of the T cell infiltrates in the primary tumors is the major prognostic parameter in CRC, hinting that tumor specific T cell immune surveillance plays a critical role in the control of tumor relapse, formation of metastases and response to treatment. We have demonstrated that tumor specific T cell responses occur in CRC patients and population of tumor antigen specific T cells are responsible for the infiltration in the tumors and for the effector functions observed in situ. Based on these observations we hypothesize that T cell responses against tumor antigens expressed on LT-TIC might trigger more efficient immune surveillance and correlate with improved CRC prognosis. Boosting pre-existing T cell responses against these antigens may improve the efficiency of tumor immunotherapy. The identification of such antigens will allow a selective therapeutic targeting of T cell responses against the populations of LT-TIC e.g. by vaccination or adoptive T cell therapy.

The activation and function of tumor specific effector T cells can be inhibited by regulatory T cells (Treg), thus underlying the important role they have in T cell based immune surveillance and control of CRC progression.

In order to lay the foundations for TIC-specific T cell based immunotherapy of CRC and for improved algorithms for prediction of CRC prognosis we are aiming to identify CRC progression-associated target antigens of spontaneous T cell and Treg responses. For this purpose we have established a whole proteome-based technology, which allowed us to identify in an unbiased manner new tumor associated target antigens of spontaneous T cell responses which are differentially expressed throughout the metastatic cascade, and for some of them we have already shown selective expression on the LT-TIC population. Furthermore we have observed that the T cell responses to these newly identified antigens were more abundant and of higher frequency than T cell responses against "canonical" tumor antigens described in the past. We have established a new method for systemic identification of target antigens triggering spontaneous Treg responses in CRC patients, which will help us to characterize the repertoire of major target antigens of tumor-specific regulatory T cells and thus will allow us to investigate their impact on the activity of tumor antigen reactive memory T cells.

We are currently working on expanding the gained information on LT-TIC associated CRC antigens and we will investigate the hypothesis that high T cell infiltrates in primary and metastatic CRC are associated with increased numbers of LT-TIC specific T cells. Their presence will be determined by utilizing HLA-multimers for selected TIC-specific antigens. Moreover we will use single cell T cell receptor (TCR)-CDR3 sequencing to identify and quantify the TIC specific TCRs. Using these two approaches we are aiming to build up a database of LT-TIC specific T cell numbers in situ and in the blood and bone marrow for consecutive correlation with patient prognosis.

Furthermore we will apply the knowledge obtained on LT-TIC associated antigens to generate LT-TIC specific CTL clones. Together with the SP2 partner we will use these clones alongside with CTL clones targeting "canonical" tumor antigens for treatment of NOD/Scid mice orthotopically transplanted with LT-TIC enriched tumor spheroids to test our hypothesis that only the LT-TIC specific CTL clones have the capability to reduce the metastatic potential and tumorigenicity of the xenotransplanted TIC spheroids and thus we will evaluate their therapeutic potential in vivo.

Team SP5

Prof. Dr. med. Ph. Beckhove, Dr. S. Stamova, M. Xydia

Project-related key publications

Halama N, Michel S, Kloor M, Zoernig I, Benner A, Spille A, Pommerencke T, von Knebel DM, Folprecht G, Luber B, Feyen N, Martens UM, Beckhove P, Gnjatic S, Schirmacher P, Herpel E, Weitz J, Grabe N, Jaeger D. Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res 2011 Sep 1;71(17):5670-7. Epub 2011 Aug 16. 

Reissfelder C, Timke C, Schmitz-Winnenthal H, Rahbari NN, Koch M, Klug F, Roeder F, Edler L, Debus J, Büchler MW, Beckhove P, Huber PE, Weitz J. A randomized controlled trial to investigate the influence of low dose radiotherapy on immune stimulatory effects in liver metastases of colorectal cancer. BMC Cancer 2011 Sep 30;11:419.

Beckhove P, Warta R, Lemke B, Stoycheva D, Momburg F, Schmitz-Winnenthal H, Ahmadi R, Dyckhoff G, Bucur M, Jünger S, Schoeler T, Lennerz V, Woelfel T, Unterberg A, Herold-Mende C 2010. Rapid T-cell based identification of tissue antigens by automated two-dimensional protein fractionation. J Clin Invest 2010 Jun;120(6):2230-42. doi: 10.1172/JCI37646. Epub 2010 May 10.

Timke C, Winnenthal HS, Klug F, Roeder FF, Bonertz A, Reissfelder C, Rochet N, Koch M, Tjaden C, Buechler MW, Debus J, Werner J, Beckhove P, Weitz J, Huber PE. Randomized controlled phase I/II study to investigate immune stimulatory effects by low dose radiotherapy in primarily operable pancreatic cancer. BMC Cancer 2011 Apr 13;11:134.

Blatner NR, Bonertz A, Beckhove P, Cheon EC, Krantz SB, Strouch M, Weitz J, Koch M, Halverson AL, Bentrem DJ, Khazaie K. In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction. Proc Natl Acad Sci U S A 2010 Apr 6;107(14):6430-5. Epub 2010 Mar 22. 

Khazaie K, Blatner NR, Khan MW, Gounari F, Gounaris E, Dennis K, Bonertz A, Tsai FN, Strouch MJ, Cheon E, Phillips JD, Beckhove P, Bentrem DJ. The significant role of mast cells in cancer. Cancer Metastasis Rev 2011 Mar;30(1):45-60. Review.

Schmitz-Winnenthal F, Pietsch D, Schimmack S, Bonertz A, Udonta F, Ge Y, Galindo L, Volk C, Zgraggen K, Koch M, Buechler M, Weitz J, Beckhove, P. Chronic pancreatitis is associated with disease-specific regulatory T cell responses. Gastroenterology 2010 Mar;138(3):1178-88. Epub 2009 Nov 18. 

Gounaris E, Blatner NR, Dennis K, Magnusson F, Gurish MF, Strom TB, Beckhove P, Gounari F, Khazaie K. T-regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposis. Cancer Res 2009 Jul 1;69(13):5490-7.

Khazaie K, Bonertz A, Beckhove P. Current developments with peptide-based human tumor vaccines. Curr Opin Oncol 2009 Nov;21(6):524-30. Review.

Bonertz A, Weitz J, Pietsch DH, Rahbari NN, Schlude C, Ge Y, Juenger S, Vlodavsky I, Khazaie K, Jaeger D, Reissfelder C, Antolovic D, Aigner M, Koch M, Beckhove P. Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. J Clin Invest 2009 Nov;119(11):3311-21. doi: 10.1172/JCI39608. Epub 2009 Oct 5.

Schuetz F, Ehlert K, Ge Y, Schneeweiss A, Rom J, Inzkirweli N, Sohn C, Schirrmacher V, Beckhove P. Treatment of advanced metastasized breast cancer with bone marrow-derived tumour-reactive memory T cells: a pilot clinical study. Cancer Immunol Immunother 2009 Jun;58(6):887-900. Epub 2008 Nov 8.

Wagner P, Koch M, Nummer D, Palm S, Galindo L, Autenrieth D, Schmitz-Winnenthal H, Schirrmacher V, Büchler M, Beckhove P, Weitz J. Detection and functional analysis of tumor infiltrating T-lymphocytes (TIL) in liver metastases from colorectal cancer. Ann Surg Oncol 2008 Aug;15(8):2310-7. Epub 2008 Jun 3.

Nummer D, Suri-Payer E, Schmitz-Winnenthal H, Bonertz A, Galindo L, Antolovich D, Koch M, Büchler M, Weitz J, Schirrmacher V, Beckhove P. Role of tumor endothelium in CD4+ CD25+ regulatory T cell infiltration of human pancreatic carcinoma. J N atl Cancer Inst 2007 Aug 1;99(15):1188-99. Epub 2007 Jul 24.

Koch M*, Beckhove P*, op den Winkel J, Autenrieth D, Wagner P, Nummer D, Specht S, Antolovic D, Galindo L, Schmitz-Winnenthal H, Schirrmacher V, Büchler M, Weitz J. Tumor Infiltrating T Lymphocytes in Colorectal Cancer. Ann Surg 2006;244:986-93. *These authors contributed equally to the study.

Sommerfeldt N, Schütz F, Sohn C, Förster J, Schirrmacher V, Beckhove P. Immunoediting in breast cancer patients: The shaping of a polyvalent and highly individual T cell repertoire in the bone marrow. Cancer Res 2006 Aug 15;66(16):8258-65.

Sommerfeldt N*, Beckhove P*, Schütz F, Choi C, Ge Y, Bucur M, Sohn C, Schneeweis A, Rom J, Pollmann D, Leucht D, Vlodavsky I, Schirrmacher V. Heparanase: a new metastasis-associated antigen recognized in breast cancer patients by spontaneously induced memory T lymphocytes. Cancer Res 2006 Aug 1;66(15):7716-23. *These authors contributed equally to the study.

Schmitz-Winnenthal H, Galindo Escobedo L, Beckhove P, Schirrmacher V, Bucur M, Ziouta Y, Volk C, Schmied B, Koch M, Antolovic D, Weitz J, Büchler M, Z'Graggen K. Specific immune recognititon of pancreatic carcinoma by patient–derived CD4 and CD8 T cells and its improvement by interferon gamma. Int J Oncol 2006 Jun;28(6):1419-28.

Müller-Berghaus J, Ehlert K, Ugurel S, Umansky V, Schirrmacher V, Beckhove P, Schadendorf D. Melanoma-reactive T cells in the bone marrow of melanoma patients: association with disease stage and disease duration. Cancer Res 2006 Jun 15;66(12):5997-6001.

Schmitz-Winnenthal H, Volk C, Bucur M, Choi C, Weitz J, Buechler M, Schirrmacher V, Z'Graggen K, Beckhove P. Tumor reactive T cells in pancreatic cancer patients and mechanism for maintenance at high frequency. Cancer Res 2005;65:10079-87.

Choi C, Witzens M, Bucur M, Feuerer M, Sommerfeldt N, Trojan A, Ho A, Schirrmacher V, Goldschmidt H, Beckhove P. Enrichment of functional CD8 memory T cells specific for MUC1 in bone marrow of patients with multiple myeloma. Blood 2005 Mar 1;105(5):2132-4. Epub 2004 Nov 23.

Steiner H, Bonsanto M, Beckhove P, Brysch M, Schuele-Freyer R, Geletneky K, Kremer P, Ranaie G, Bauer H, Kunze S, Schirrmacher V, Herold-Mende C. Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit. J Clin Oncol 2004 Nov 1;22(21):4272-81. Epub 2004 Sep 27.

Feuerer M, Beckhove P, Mahnke Y, Hommel M, Kyewski B, Hamann A, Umansky V, Schirrmacher V. Bone marrow microenvironment facilitating dendritic cell: CD4 T cell interactions and maintenance of CD4 memory. Int J Oncol 2004 Oct;25(4):867-76.

Karcher J*, Dyckhoff G*, Beckhove P*, Reisser C, Brysch M, Ziouta Y, Helmke B, Weidauer H, Schirrmacher V, Herold-Mende C. Antitumor vaccination in patients with head and neck squamous cell carcinomas with autologous virus-modified tumor cells. Cancer Res 2004 Nov 1;64(21):8057-61. *These authors contributed equally to the study.

Beckhove P, Feuerer M, Dolenc M, Schuetz F, Choi C, Sommerfeldt N, Schwendemann J, Ehlert K, Altevogt P, Bastert G, Schirrmacher V, Umansky V. Specifically activated memory T cell subsets from cancer patients recognize and reject xenotransplanted autologous tumors. J Clin Invest 2004 Jul;114:67-76.

Bai L, Beckhove P, Feuerer M, Umansky V, Choi C, Solomayer F, Diel I, Schirrmacher V. Cognate interactions between memory T cells and tumor antigen-presenting dendritic cells from bone marrow of breast cancer patients: bidirectional cell stimulation, survival and antitumor activity in vivo. Int J Cancer 2003 Jan 1;103(1):73-83.

Feuerer M*, Beckhove P*, Garbi N*, Mahnke Y, Limmer A, Hommel M, Hämmerling G, Kyewski B, Hamann A, Umansky V, Schirrmacher V. Bone marrow as a priming site for T cell responses to blood-borne antigen. Nature Med 2003 Sep;9(9):1151-7. Epub 2003 Aug 10. *These authors contributed equally to this study.

Schirrmacher V, Feuerer M, Fournier P, Ahlert T, Umansky V, Beckhove P. T-cell priming in bone marrow: the potential for long-lasting protective anti-tumor immunity. Trends Mol Med 2003 Dec;9:526-34.

Feuerer M*, Beckhove P*, Bai L, Solomayer E, Bastert G, Diel I, Pedain C, Oberniedermayr M, Schirrmacher V, Umansky V. Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow. Nature Med 2001 Apr;7(4):452-8. *These authors contributed equally to the study.

Khazaie K, Prifti S, Beckhove P, Griesbach A, Russell S, Collins M, Schirrmacher V. Persistence of dormant tumor cells in the bone marrow of tumor cell-vaccinated mice correlates with long-term immunological protection. Proc Natl Acad Sci U S A 1994 Aug 2;91(16):7430-4.

To top