TIL-REP

Dynamics of the tumor infiltrating lymphocyte repertoire in melanoma and pancreatic cancer

In many types of cancer the presence of tumor-infiltrating lymphocytes (TIL) is associated with better survival. This suggests that the immune system can recognize and fight tumors. In advanced cancer the dominant scenario is often one of immunosuppression, where for example TIL are rendered impotent through inhibitory factors secreted by tumor cells.
Therapeutic efforts aim to revert this situation, e.g. by blocking negative signals using therapeutic antibodies (e.g. Ipilimumab). The in vitro expansion and re-infusion of TIL (so called TIL therapy) can also (re)activate the anti-tumoral immune response.
Under such optimized circumstances the inhibition of tumor growth by the immune system can be remarkable, even in metastatic cancer. This has been studied particularly well in patients with malignant melanoma. Many studies have shown that the success of such therapies depends on the presence of tumor-reactive T-cells. However, it is not yet fully understood exactly which T-cells are responsible for mediating these positive effects.

Fig. 1: TCR-Analyzsis as a tool to study the TIL repertoire, similified schematic representation*
1-3. Each T-cell is equipped with a unique receptor. 4. If a T-cell is activated, e.g. through contact with a tumor, it starts to divide and forms a so-called T-cell "clone". All cells of this clone carry the same T-cell receptor. 5. The "size" of a clone, meaning the number of cells with the same receptor, can be measured by T-cell receptor sequencing.
* the T-cell receptor consists of an alpha and a beta chain/subunit which are rearranged in a similar manner, 1-3 show only the beta-chain

The TIL-REP consortium will investigate the composition and dynamic changes of the TIL repertoire as well as its clinical implications. To this end we are pursuing three complimentary approaches:

Analysis of the TIL repertoire in human tumor biopsies of melanoma and pancreatic ductal adenocarcinoma by phenotypic characterization (measurement of characteristic cell surface and activation markers) and T-cell receptor (TCR) sequencing (see Fig. 1)

Examination of the clonal dynamics of the TIL response in a well-defined pre-clinical model

Establishment of a data-driven mathematical model to quantify and thus better understand the fundamental processes governing the development of the TIL repertoire and simulate its response to immunotherapy

Our systems medicine approach (see Fig 2) combines data from mathematical models, pre-clinical experiments and patient-based research to better understand tumor-immune interactions, develop biomarkers for immunotherapy trials and improve cancer patient care.
To achieve these goals we are working in an interdisciplinary team, allowing us to address our research questions from a theoretical, (cell)biological and clinical perspective (see Fig 3).

Fig. 3: The five subprojects of the TIL-REP junior consortium investigate the composition and dynamics of the T-cell repertoire. The subproject leaders contribute their specialized knowledge from the fields of pre-clinical mouse models (Diken), computational biology (Floßdorf), human T-cell biology (Poschke), melanoma (Hassel) and pancreatic cancer (Strobel) to increase our understanding of biology and improve cancer patient care.

Subprojects in TIL-REP:

SP 1 TIL dynamics in a mouse model of melanoma

SP 2 Data-based mathematical modeling of the anti-tumor T-cell response

SP 3 TIL repertoire in melanoma and pancreatic ductal adenocarcinoma

SP 4 Tumor-reactive T-cells and response to immune checkpoint blockers

SP 5 TIL dynamics in pancreatic ductal adenocarcinom

Keywords: tumor-infiltrating lymphocytes, immunotherapy, T-cell receptor repertoire, next-generation sequencing, pancreatic cancer, melanoma, vaccination, immuno-stimulatory antibodies