Rewire the lymph node niche to instruct T cell immunity

Projektinformationen

REWIRE

ID Finanzhilfevereinbarung: 101115832

DOI

10.3030/101115832

EK-Unterschriftsdatum 30 Oktober 2023

Startdatum 1 Januar 2024

Enddatum 31 Dezember 2028

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 1 499 730,00

EU-Beitrag

€ 1 499 730,00

Koordiniert durch

CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH
Austria

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

Berichtszeitraum: 2024-01-01 bis 2026-06-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

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.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

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.