A new study in ovarian cancer found that using IgA-based antibodies produced by B cells may represent new immunotherapeutic agents for tumors resistant to conventional immune checkpoint blockade, which are currently focused on T cell-centric approaches.
By design, immunotherapies are designed to boost the body’s T cells to recognize and destroy cancer cells, but ovarian cancers seem to evade them or remain resistant to their activity. This despite the fact that most ovarian cancer appear to be infiltrated with activated T cells. As a result, ovarian patient outcomes following immunotherapy have largely proven disappointing.
Researchers from the Moffitt Cancer Center have discovered potential reasons why humoral immunity, or antibody-based immunity, appears to be associated with better outcomes in some ovarian cancers, potentially opening a new line of therapeutic intervention.
With assistance from helper T cells, B cells will differentiate into plasma B cells that can produce antibodies against a specific antigen. Earlier research has found that patients with plasma and memory B cells could respond better to immunotherapies
To characterize the role of B cells in ovarian cancer, the Moffitt team analyzed 534 samples from patients with high-grade serous ovarian cancer. As expected, they found that patients who had a higher levels of B cells or B cell-derived plasma cells had better outcomes.
The reason appeared to be linked to the type of antibody produced by the B cells. B cells produce antibodies with one five types of B cell receptors on their surface: IgM, IgD, IgG, IgE or IgA. Each regulates different B cell signaling pathways.
In this study, they discovered that the antibodies produced by B and plasma cells were predominantly of the IgA subtype, followed by IgG.
“We found that the presence of IgA regulated downstream signaling pathways of the ovarian cancer cells. Specifically, IgA resulted in inhibition of the RAS signaling pathway, which is known to contribute to ovarian cancer development,” said Jose Conejo-Garcia, M.D., Ph.D., chair of Moffitt’s Immunology Department.
The team concluded that RAS inhibition sensitized the tumor cells to T cell mediated cell killing, produced by both novel CAR T cells and tumor-infiltrating lymphocytes. The team also learned that that IgA secreted by the B cells recognized specific ovarian tumor cell surface markers and stimulated other immune cells called myeloid cells to target ovarian cancer cells for destruction.
Therefore, it appears that IgA produced in the ovarian cancer microenvironment antagonizes the growth of ovarian cancer by governing coordinated activity from tumor cells, T cells, and B cells — representing a possible new therapeutic direction.
“These findings suggest that immunotherapies that augment B cell responses may be more effective than approaches that focus on T cells, particularly for malignancies that are resistant to checkpoint inhibitors,” the authors conclude.
These findings indicate that immunotherapies that boost both coordinated B and T cell responses against human ovarian cancer are likely to show increased therapeutic benefit.
