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Artificial induction of tertiary lymphoid structures (TLS) in tumors using intratumoral mRNAs to evaluate its synergy with immune checkpoint inhibitors

Project description

Inducing lymphoid structures for enhanced cancer immunotherapy

Tertiary lymphoid structures (TLSs) are ectopic lymphoid tissues formed at sites of persistent or chronic inflammation, including some tumours. Although TLS presence has been associated with improved prognosis and better response to immunotherapy, not all patients develop these immune structures. With the support of the Marie Skłodowska-Curie Actions programme, the TLSaRNA project aims to investigate novel therapies to induce TLS through intratumoural mRNA injection. The working hypothesis is that TLS may have a synergistic effect with immunotherapy. Moreover, the study will employ advanced techniques to uncover the role of tumour-specific B cells and antibodies.

Objective

Tertiary lymphoid structures (TLS) are ectopically generated lymphoid structures with some level of cellular organisation similar to the secondary lymphoid organs, characterised by having a B-cell zone adjacent to a T-cell zone. The presence of tumor immune infiltrates, especially in the form of TLS, has been linked to a better cancer prognosis in different types of tumor and improved response to immune checkpoint inhibitors (ICB). However, interestingly, not all the patients develop TLS and the cellular composition and organisation within the structures can vary. Specifically, the role of B cells in the tumor microenvironment is controversial, while some studies have reported a pro-tumoral effect, possibly through differentiation of regulatory B cells, metadata shows a strong association between the presence of a transcriptional B cell profile on the tumors and the improved patient outcome. Moreover, the presence of B cells in the tissue microenvironment is also positively associated with an improved response to ICB. However, even though these strong statistical associations and the relevance of TLS in the cancer prognosis, still little is known about the mechanisms underlying their function and the specific role of B cells in the anti-tumoral response elicited. In this proposal, we will study novel therapies for artificial TLS induction by using intratumoral injection of mRNAs encoding for specific cytokines. We will deeply characterise the synergy between immunotherapy treatments and TLS in the tumor development by using the state-of-the art spatial transcriptomics and immunophenotyping. Finally, we will decipher the function of tumor-specific B cells on the tumor microenvironment and the relevance of tumor-specific secreted antibodies in the overall anti-tumoral response. Ultimately, the knowledge generated with this proposal will provide relevant information to guide future immunotherapy treatments.

Fields of science (EuroSciVoc)

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Funding Scheme

HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

(opens in new window) HORIZON-MSCA-2023-PF-01

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Coordinator

FUNDACION PARA LA INVESTIGACION MEDICA APLICADA FIMA
Net EU contribution
€ 181 152,96
Address
AVENIDA DE PIO XII 55
31008 Pamplona
Spain
Region
Noreste Comunidad Foral de Navarra Navarra
Activity type
Research Organisations
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Total cost
No data