PhD Defense: From Evasion to Elimination; Enhancing IgA therapy through myeloid checkpoint inhibition

This thesis investigates the use of IgA antibodies as a new approach in cancer treatment, offering an alternative to the IgG antibodies currently used in immunotherapy. While IgG antibodies are widely used due to their stability and long half-life, they are not effective for everyone, and some patients develop resistance, highlighting the need for new treatments.

IgA antibodies, particularly in their monomeric form, offer distinct advantages by activating various immune cells, such as neutrophils, through the Fc-alpha receptor (CD89). Neutrophils, which are abundant in the body, can kill cancer cells when activated. However, producing IgA antibodies on a large scale is challenging due to their complex structure.

To overcome these challenges, we developed a modified IgA antibody, called IgA3.0, which is more stable and easier to produce. IgA3.0 showed strong anti-cancer responses in our experiments by effectively activating neutrophils. Additionally, our study showed that IgA works best when tumor cells have high levels of specific tumor antigens, potentially reducing side effects by sparing healthy cells.

Furthermore, checkpoint molecules like CD47 on tumor cells inhibit immune responses by binding to SIRPα on myeloid cells, including neutrophils. Our research showed that combining IgA therapy with CD47 blockade significantly improved anti-tumor responses. This combination increased neutrophil infiltration and activity in the tumor microenvironment, leading to better tumor control. Therefore, blocking checkpoint molecules is a promising strategy to enhance the efficacy of IgA. 

In summary, this study shows that IgA antibodies can effectively activate neutrophils to fight cancer, offering a promising alternative for patients who do not respond to current IgG-based therapies.