Patients with advanced ovarian cancer have a dismal 5-year survival rate of only 40 percent, in part because they typically do not have a strong response to immunotherapy drugs designed to activate tumor-killing T cells.
With that in mind, researchers at Moffitt Cancer Center in Tampa, Fla., investigated a different treatment approach focused on the therapeutic potential of memory B cells and plasma cell infiltrates, which previously have been associated with improved outcomes in patients with ovarian cancer.
For the study, the researchers stained a panel of 534 annotated high-grade serous ovarian cancers from three separate patient cohorts with B-cell and T-cell markers. They discovered that the predominance of the B-cell receptors were of the IgA subtype, the presence of which resulted in the inhibition of the RAS signaling pathway, a known contributor in the development of ovarian cancer.
Detailing their findings in Nature, the researchers describe a possible new platform for identifying target malignancies spontaneously recognized by intratumoral B cell-derived antibodies, and also suggest immunotherapies that augment B-cell responses may be more effective than T-cell focused drugs, particularly for malignancies resistant to checkpoint inhibitors (2021; doi.org/10.1038/s41586-020-03144-0).
Recently, Jose Conejo-Garcia, MD, PhD, Chair of Moffitt Cancer Center's Immunology Department and lead investigator for the study, shared additional insight into the findings from the new research with Oncology Times.
What inspired you to investigate this research question?
Conejo-Garcia: "We have been working on the immunobiology of ovarian cancer for nearly 2 decades. A paradox of this disease is that, while there is universal consensus about the importance of the anti-tumor immune response for the patients' outcome, existing immunotherapies have produced so far disappointing results. However, anti-cancer immunotherapies are heavily focused on T lymphocytes. Since recent reports indicate that ovarian tumors are also heavily infiltrated by B cells, we aimed to dissect the nature and role of these responses."
Briefly, what are the key takeaways from the results of your study?
Conejo-Garcia: "The main takeaway is that spontaneous antibody responses are dominated by IgA and, to a lesser extent, IgG, and therefore both strong and prolonged, as well as relevant for the patients' outcome. These antibodies target multiple antigens accessible on the tumor cell, or present in molecules secreted to the tumor microenvironment. IgA exerts anti-tumor activity, first, through internalization and passage through tumor cells, which express the IgA/IgM PIGR receptor, similar to enterocytes in the gut. In addition, IgA redirects macrophages (and likely neutrophils) against tumor cells, causing cytotoxic killing."
Were there any unexpected or surprising results in your study?
Conejo-Garcia: "The first surprise was the magnitude of the IgA response in ovarian cancer. In addition, we were surprised to find that virtually all ovarian tumors express the IgA receptor PIGR. In fact, we believe that this is a common occurrence in tumors of epithelial origin. Accordingly, IgA transcytoses (passes) through the tumor cell, with unexpected consequences in terms of dampening tumor-promoting pathways and sensitizing tumor cells to T cell-mediated killing."
Is there anything about the results of your study that others might get wrong?
Conejo-Garcia: "For years, humoral responses have been associated with tumor-promoting activities. We believe that this is the result of mouse models that progress too rapidly and do not reflect the pathophysiology of human tumors (at least epithelial malignancies). An array of recent and emerging manuscripts focused on human cancer are demonstrating that, as we teach students in the first classes of our immunology lectures, T and B cells work in coordination and reinforce each other.
"In addition, we are not sure about the relative contribution of IgA versus IgG in other tumors, and it would be premature to extrapolate the role of IgA to other malignancies. However, based on the analyses of TCGA datasets and established cell lines, it seems that epithelial tumor cells of multiple origins have the capacity to bind IgA and, therefore, the possibility to internalize it."
What are the potential clinical implications, if any, of your research?
Conejo-Garcia: "There are multiple clinical implications. First, we provide a mechanistic rationale for using IgA as an alternative tool for novel immunotherapies, as opposed to the current exclusive use of IgG. Second, we provide new methods for characterizing the targets recognized by antibodies produced by tumor-associated B cells. A significant fraction of these targets are expressed on the tumor cell surface, and we are currently cloning reactive antibodies to use them in CAR T-cell immunotherapies, as well as direct immunotherapeutic targets. Third, as current anti-cancer immunotherapies are primarily T cell-centric, our study also provides a rationale for a new generation of immunotherapies (i.e., vaccines) that aim to enhance coordinated T- and B-cell responses, as opposed to keep ignoring the humoral anti-cancer response."
What further investigations need to be done on this research topic?
Conejo-Garcia: "Besides determining whether these results can be extrapolated to other epithelial malignancies, we are now characterizing the activity and anti-tumor potential of specific tumor-derived antibodies, which we expect to develop in the form of novel immunotherapeutics. In addition, we are investigating the nature and role of B cells and plasma cells producing antibodies at tertiary lymphoid structures, which are present in ~20 percent of ovarian carcinomas and are, as in other diseases, associated with improved outcome."
Is there anything else about your research that you would like add?
Conejo-Garcia: "We are glad that the field is making a U-turn and applying a more holistic view of the anti-tumor immune response, whereby the coordinated action of multiple cell types and elements of the immune system work in coordination. A welcome change from a narrow view of T cells as the only drivers of immune pressure against malignant progression."
Chuck Holt is a contributing writer.