This dissertation of Marta Requesens Rueda investigates how the immune system can be harnessed more effectively to fight cancer, with a focus on Immune Checkpoint Inhibitors (ICIs) in particular. ICIs work by releasing the immune system’s natural "brakes," allowing it to destroy cancer cells more efficiently. While these therapies have revolutionized treatment for some cancer types, many patients still show limited or no response, and the underlying reasons remain unclear.
The research centers on uterine and colon cancers, which often exhibit genomic instability, a high number of DNA mutations. This genomic chaos can make tumors more visible to the immune system by producing abnormal proteins, but it also allows cancer to evolve, evade immune attacks, and become more resistant. A key challenge studied is the loss of MHC-I molecules, which normally help immune cells detect cancer. Interestingly, the research shows that even without MHC-I, immune responses can be reactivated by engaging other immune cell types, particularly through enhanced cooperation between them.
Another focus is on tertiary lymphoid structures (TLS), organized clusters of immune cells that form around tumors and are linked to better clinical outcomes. The study reveals how ICIs can promote TLS formation, and how interactions within these structures, especially involving B cells that produce tumor-targeting antibodies, contribute to tumor control and better patient outcomes. Finally, a clinical trial using ICI treatment before surgery demonstrated that such therapy is both safe and effective, boosting immune activity in tumors and nearby lymph nodes. These findings highlight new avenues to improve immunotherapy and personalize cancer treatment.
