Regulation of T Lymphocyte Function in Tumors group

Pierre van der Bruggen, Member Didier COLAU, Senior Investigator Daniele GODELAINE, Senior Investigator Nathalie DEMOTTE, Postdoctoral Fellow Isabelle JACQUEMART, Postdoctoral Fellow Claude WILDMANN, Research Associate Violaine FRANÇOIS, PhD Student Emilie GAUTHY, PhD Student Grégoire WIEERS, MD, PhD Student Débora PICCOLO, Research Assistant Laurie VANBIERVLIET, Technician Vinh HA THI, Technician

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The group led by Pierre van der Bruggen identified in the early 1990s the first gene coding for a human tumor antigen recognized by cytolytic T lymphocytes (CTL). It was named MAGE-A1. It took several years to define antigenic peptides encoded by genes such as those of the MAGE gene family. These peptides have been used in therapeutic vaccination trials of cancer patients. Efforts have been devoted to set up assays that accurately monitor T cell responses to cancer vaccines, including regulatory T cells.

The group further analyzed the properties of anti-tumor CTL clones. The differentiation of naive T cells into memory and effector cells is marked by changes in the expression of surface molecules such as CCR7 and CD45. They found that the expression of CD45RA on CCR7- CD8+ T cells is indicative of the time elapsed since the last antigenic stimulation rather than the signature of a terminally differentiated status with an incapacity to proliferate.

Anti-tumor T cells are present in tumor metastases that are progressing. This spontaneous anti-tumor T cell response must become ineffective at one point, possibly because the effector cells have become unable to exert their function, a state known as anergy. This anergy could result from inhibitory processes elicited by tumor cells. The group is currently involved in the study of T cell anergy. We have identified a novel mechanism causing anergy of human tumor-infiltrating lymphocytes, and established a new approach to correct this anergy in vitro. We observed that exhausted CTL clones and anergic tumor-infiltrating lymphocytes had lost the colocalization of T cell receptor (TCR) and CD8. Effector function and TCR-CD8 colocalization were restored with competitive galectin binders, such as sugars, suggesting that the binding of TCR to galectin plays a role in the distancing of TCR from CD8. Administration of competitive galectin binders may be a therapeutic option to induce a more efficient and long-lasting anti-tumor immune response.

Selected publications

1. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, Knuth A, Boon T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 1991;254:1643-7
2. Boon T, Coulie PG, Van den Eynde B, van der Bruggen P Human T cell responses against melanoma. Annu Rev Immunol 2006;24:175-208.
3. van der Bruggen P, Zhang Y, Chaux P, Stroobant V, Panichelli C, Schultz ES, Chapiro J, Van den Eynde BJ, Brasseur F, Boon T. Tumor-specific shared antigenic peptides recognized by human T cells. Immunol Rev 2002;188:51-64.
4. Carrasco J, Van Pel A, Neyns B, Lethé B, Brasseur F, Renkvist N, van der Bruggen P, van Baren N, Paulus R, Thielemans K, Boon T, Godelaine D. Vaccination of a melanoma patient with mature dendritic cells pulsed with MAGE-3 peptides triggers the activity of nonvaccine anti-tumor cells. J Immunol 2008;180:3585-93.
5. Godelaine D, Carrasco J, Brasseur F, Neyns B, Thielemans K, Boon T, Van Pel A. A new tumor-specific antigen encoded by MAGE-C2 and presented to cytolytic T lymphocytes by HLA-B44. Cancer Immunol Immunother 2007;56:753-9.
6. Zhang Y, Renkvist N, Sun Z, Schuler-Thurner B, Glaichenhaus N, Schuler G, Boon T, van der Bruggen P, Colau D. A polyclonal anti-vaccine CD4 T cell response detected with HLA-DP4 multimers in a melanoma patient vaccinated with MAGE-3.DP4-peptide-pulsed dendritic cells. Eur J Immunol 2005;35:1066-75.
7. Carrasco J, Godelaine D, Van Pel A, Boon T, van der Bruggen P. CD45RA on human memory CD8 T cells is a marker for the time elapsed since the last antigenic stimulation. Blood 2006;108:2897-905.
8. Demotte N, Colau D, Ottaviani S, Godelaine D, Van Pel A, Boon T, van der Bruggen P. A reversible functional defect of CD8+ T lymphocytes involving loss of tetramer labeling. Eur J Immunol 2002;32:1688-97.
9. Demotte N, Stroobant V, Courtoy PJ, Van der Smissen P, Colau D, Luescher IF, Hivroz C, Nicaise J, Squifflet JL, Mourad M, Godelaine D, Boon T, van der Bruggen P. Restoring the association of the T cell receptor with CD8 reverses anergy in human tumor-infiltrating lymphocytes. Immunity 2008;28:414-24.
10. Graham SP, Pelle R, Honda Y, Mwangi DM, Tonukari NJ, Yamage M, Glew EJ, de Villiers EP, Shah T, Bishop R, Abuya E, Awino E, Gachanja J, Luyai AE, Mbwika F, Muthiani AM, Ndegwa DM, Njahira M, Nyanjui JK, Onono FO, Osaso J, Saya RM, Wildmann C, Fraser CM, Maudlin I, Gardner MJ, Morzaria SP, Loosmore S, Gilbert SC, Audonnet JC, van der Bruggen P, Nene V, Taracha EL. Theileria parva candidate vaccine antigens recognized by immune bovine cytotoxic T lymphocytes. Proc Natl Acad Sci U S A 2006;103:3286-91.

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