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

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

Cancer immunotherapy exploits the ability of the host immune system to control the development and progression of tumours. Even though the success of immune checkpoint inhibitors in the treatment of many different tumours, still only a fraction of patients can benefit of them, possibly because the low numbers of intratumoural immune cells in the no-responders and their unresponsiveness state. Therefore, the generation of new therapies aiming to potentiate the immune infiltration can be crucial to improve current treatments. Not only the infiltration of the immune system is important for generating anti-tumoral responses, also their intratumoural organisation. Under situations of chronic inflammation such as cancer, ectopically generated immune structures called tertiary lymphoid structures (TLS) may emerge. TLS have a similar level of organization than the secondary lymphoid organs, characterised by having a B-cell zone adjacent to a T-cell zone, and interestingly their presence has been statistically correlated to a better cancer prognosis in different types of tumours and improved response to immune checkpoint inhibitors (ICB). However, 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 tumour 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 tumours 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 (i) study novel therapies for artificial TLS induction; (ii) characterise their combination with ICBs; and (iii) decipher the function of B cells on the tumour microenvironment. Ultimately, the knowledge generated with this proposal will provide relevant information to guide future immunotherapy treatments.

Data: CORDIS, © European Union