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

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.