Rewire the lymph node niche to instruct T cell immunity

Project Information

REWIRE

Grant agreement ID: 101115832

DOI

10.3030/101115832

EC signature date 30 October 2023

Start date 1 January 2024

End date 31 December 2028

Funded under

• European Research Council (ERC)

Total cost

€ 1 499 730,00

EU contribution

€ 1 499 730,00

Coordinated by

CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH
Austria

Periodic Reporting for period 1 - REWIRE (Rewire the lymph node niche to instruct T cell immunity)

Reporting period: 2024-01-01 to 2026-06-30

Summary of the context and overall objectives of the project

The lymph node is a key tissue initiating immune responses. In order for an effective immune response to take place, different types of immune cells need to meet and engage in contacts that result in information exchange and immune cell activation. These contacts are orchestrated in the lymph node. The lymph node has many spatially organized microenvironments that all attract specific immune cell subsets and thereby regulate which immune cells can become activated, and which ones become suppressed. In the context of cancer, tumor-derived factors reach the lymph node and likely affect how immune cells get activated. This is of high relevance, since the tumor-draining lymph node is the tissue where tumor-directed immune responses are initiated. Therefore, we are studying tumor-derived changes in the tumor-draining lymph node environment. We aim to understand immunosuppressive mechanisms that can be reverted by future immunotherapy approaches targeting the lymph node.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In the ongoing project REWIRE, we have so far generated a spatial roadmap of the tumor-draining lymph node, and have identified tissue microniches, or tissue neighborhoods, that are changed upon tumor progression. Some of these lymph node microniches are strongly compressed, whereas others expand in the presence of a tumor. Based on what spatial neighborhoods dominate the lymph node and what immune cell subtypes are present, we can assess whether an active immune response is being triggered, or whether immunosuppressive mechanisms are dominant. Indeed, in tumor-draining lymph nodes, we found indication for both immune-activating, as well as immune-suppressive mechanisms acting at the same time. Thus, we can now focus on validating which are the most important mechanisms with the biggest impact. Further, we can now develop strategies to either block immunosuppressive mechanisms in the tumor-draining lymph node; or to stimulate immune-activating mechanisms. Both are promising strategies to boost anti-tumor immunity.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

So far, comprehensive understanding of how tumors reprogram tumor-draining lymph nodes, especially regarding the spatial tissue architecture, is lacking. Therefore, our results are a significant step towards understanding the basic biology of how tumor-directed immune responses are generated, and what are immunosuppressive mechanisms that inhibit immune activation in tumor-draining lymph nodes. To fully leverage this knowledge, and to develop clinically feasible strategies to target the lymph node, more research is needed focusing on validating the functional relevance of the observed mechanisms; as well as to develop therapeutic strategies to target those mechanisms, e.g. cell-based therapies. As a next step in the project, we aim to decipher what immunosuppressive mechanisms have the biggest impact on the lymph node, and what would be the ideal target for future (pre)clinical development.