The prognosis for ovarian cancer is poor, with an estimated five-year survival of only 40% for advanced disease, the stage at which most ovarian cancers are diagnosed. These poor results are partly due to the lack of effective therapies for advanced disease and relapses. Immunotherapies show promise for many cancers; However, studies have shown that ovarian cancer patients do not respond strongly to existing medications.
In a new article published in Nature, researchers at the Moffitt Cancer Center show why some ovarian cancer patients develop better than others and suggest possible approaches to improve patient outcomes.
Immunotherapeutics activate T cells, a type of immune cell, to defend themselves against tumor cells. Immunotherapies are approved to treat a variety of cancers and have changed the standard of care and patient outcomes significantly. In ovarian cancer, however, clinical trials of immunotherapies to stimulate T cells have shown modest response rates.
Studies have shown that cancer patients with a higher presence of other immune cells, such as plasma and memory B cells, may respond better to immunotherapies, but how these cell types promote better outcomes is unclear. Moffitt researchers wanted to confirm whether antibodies produced by these cells are associated with better results and to evaluate how these cells contribute to the spontaneous anti-tumor immune response against ovarian cancer.
The researchers analyzed a group of 534 samples from ovarian cancer patients and found that patients with higher infiltration of B-cells or B-cell-derived plasma cells had better results. B cells are a type of immune cell that produce antibodies and express one of five types of B cell receptors on their surface: IgM, IgD, IgG, IgE, or IgA. These isotypes regulate various B-cell signaling pathways and control B-cell processes.
The surprise came when, on further analysis of the samples, the Moffitt team 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 regulates the downstream signaling pathways of ovarian cancer cells. In particular, IgA inhibited the RAS signaling pathway, which is known to contribute to the development of ovarian cancer. “
Jose Conejo-Garcia, MD, Ph.D., chairman of the Moffitt Department of Immunology
This inhibition of RAS sensitized the tumor cells to the T-cell-mediated killing of cells produced by both novel CAR-T-cells and tumor-infiltrating lymphocytes. The team also assessed that IgA and IgG secreted by the B cells recognized specific surface markers for ovarian tumor cells and stimulated other immune cells called myeloid cells to target ovarian cancer cells for destruction.
These data provide new insights into how components of the immune system regulate ovarian cancer progression and offer new opportunities for the development of improved targeted drugs. This includes a repertoire of tumor-derived antibodies that can be used effectively as novel immunotherapeutic agents. In addition, the study provides a mechanistic rationale for integrated antibody responses in the development of novel immunotherapies that were previously based on T-cell-centered approaches.
“The results show that immunotherapies that enhance both coordinated B- and T-cell responses to ovarian cancer, an immunogenic disease currently resistant to checkpoint inhibitors, are likely to demonstrate superior therapeutic benefit,” said Subir Biswas, Ph.D., lead author and postdoctoral fellow in the Conejo Garcia laboratory.
The study will eventually pave the way for the use of antibodies other than IgG as immunotherapeutic agents for at least tumors currently resistant to conventional blockade of the immune checkpoint.
H. Lee Moffitt Cancer Center & Research Institute
Biswas, S. et al. (2021) IgA transcytosis and antigen recognition control immunity against ovarian cancer. Nature. doi.org/10.1038/s41586-020-03144-0.