Session IV: DCs go all the way
Friday March 31
9.00 Sophie Acton, London, United Kingdom
“Dendritic cells control lymph node expansion “
Lymph node swelling is a classical hallmark of immunity. This expansion is observed by doctors, researchers and patients, yet as obvious as this process is, our understanding of the remodelling mechanisms involved are in their infancy. Lymph node remodelling is rapid and yet completely reversible, occurring countless times throughout our lifetimes. The architecture of lymphoid organs is key to the effective operation of our immune system and is dictated by structures formed by non-haematopoetic stromal cells, including endothelial cells, and fibroblasts. Beyond their structural roles, stromal cells play an active role in immune responses, and the field of stromal immunology has become one of the most dynamic and exciting areas of immunology research. In the lab we focus on the changing behaviour of fibroblastic reticular cells (FRCs) throughout cycles of lymph node remodelling. We have shown that dendritic cells communicate with FRCs through engagement between CLEC-2 and podoplanin, driving necessary changes for lymph node expansion. These findings add to our understanding of how lymph node remodelling occurs and is resolved, repeatedly; to understand immunity in a whole organ context.
9.45 John B.A.G. Haanen, NKI Amsterdam
‘Adoptive T cell therapy: What do T cells recognize on cancer cells?’
In the past years immunotherapy of cancer has proven to be an important new pillar in anticancer treatment, next to surgery, radiotherapy and chemo- or targeted therapy. Especially, treatment with immune checkpoint inhibitors like anti-CTLA4, and probably even more, anti-PD-1/PD-L1 and adoptive cell therapy using TILs, have shown to improve life expectancy of patients with metastatic disease. Immune checkpoint inhibitors both induce new T cell responses (anti-CTLA4) to cancer cells or re-invigorate immunosuppressed T cells in the tumor environment. Naturally, the latter could only work when tumor-specific T cells were present to start with. Similarly, TILs could only work if they contained tumor-specific T cells that were expanded before cell transfer in patients.
At the Schumacher/Haanen lab technology has been developed over past years to allow semi high-throughput screening of tumor-specific T cells mostly in metastatic melanoma patients and to some extend also in other tumor types. We found that both shared tumor antigen-specific and neo-antigen-specific T cells can be found in either peripheral blood or in TILs from metastatic lesions. We were able to show that the frequency of neo-antigen specific T cells (both CD4 and CD8) is present in the majority of patients tested so far. In addition, their frequency among TIL was in general many fold higher compared to shared antigen-specific T cells. Therefore, at least for tumor types harboring many mutations, evidence is accumulating that neo-antigen specific T cells appear to play a major role in the activity of immunotherapies that are being observed (melanoma, NSCLC, MMR deficient tumors).
Although immunotherapy is an important breakthrough, still many patients do not respond to immunotherapy. One of the reasons may be that the T cells at the tumor sites are so exhausted that other measures are required to overcome this. However, it is important to verify first whether these non-responding tumors harbor tumor-specific T cells. We set up a technology that allows us to study whether TILs contain tumor-specific T cells by cloning TCRs from these TILs. We transduced non-exhausted autologous T cells with these TCRs coming from TILs and tested the transduced T cells for tumor-reactivity. Preliminary data will be shown.
10.30 Coffee break