Location-Dependent B-cell Function in Glioblastoma

Glioblastoma is one of the most aggressive cancers, likely because it is diagnosed at an advanced stage and its ability to create an immunosuppressive environment (1). Conventional therapies such as surgery, radiotherapy, and pharmacotherapy do not improve patient survival. For these reasons, immunotherapy is considered a promising treatment. Although therapeutic response in preclinical glioblastoma models is observed with immunotherapy, clinical trials in patients with recurrent glioblastoma have been disappointing, and more studies are underway in the first-line treatment setting (1). As is the case for many other tumors, the most studied immune cell types in glioblastomas are T cells and myeloid cells. Glioblastoma-associated T cells are skewed toward immunosuppressive T cells (known as regulatory T cells) to the detriment of cytotoxic T lymphocytes (CTL), which have tumor killing activities. The origin of the glioblastoma immunosuppressive microenvironment is still unclear, although myeloid cells are suspected to be key mediators. Among these myeloid cells, microglia, tumor-associated macrophages, and immature myeloid cells (known as myeloid-derived suppressor cells, or MDSCs) are the most studied. These can suppress CTL activity and promote regulatory T-cell formation. For this reason, several efforts are underway to develop new drugs that target myeloid cells and either change their activity or remove them altogether (1). Whether additional immune cell types play a role in establishing glioblastoma-associated immunosuppression is unclear. However, the identification of additional immune cell players would allow them to be targeted, providing new treatment approaches against this devastating disease.

The work by Lee-Chang and colleagues investigated the role of B cells in glioblastoma (2). B cells share several features with T cells, for example, the ability to generate a large repertoire of unique surface receptors while performing very different functions such as antibody generation. Investigations on the role of B cells in cancer have so far yielded contradicting results, with some studies indicating a tumor-promoting role and others suggesting anticancer activity (3). A major finding of Lee-Chang and colleagues' study is that not all B cells are equal. Local elimination of tumor-associated B cells had a positive outcome, whereas global B-cell depletion (which removes also tumor-associated B cells) yielded no therapeutic benefit. This observation helps to explain previous contradicting data on whether B cells should be eliminated or supported in patients with cancer and reinforces the hypothesis that B cells might possess a dual role depending on their localization: protumorigenic functions inside a tumor versus antitumor activities systemically. Mechanistically, it was suggested that MDSCs induced an immunosuppressive phenotype in B cells via the release of extracellular vesicle–associated PD-L1. Just like with T cells, immunosuppressive B cells are referred to as regulatory B cells.

More work needs to be done to clarify other contradicting points, such as the observation that tertiary lymphoid structures (which are composed mainly of B cells) are generally associated with improved survival, thus indicating an antitumor activity of intratumoral B cells, which is in contrast with the work from Lee-Chang and colleagues. As novel immunotherapeutic targets and combination therapies are validated and tested in the clinic, the work by Lee-Chang and colleagues is a timely reminder to consider potential approaches to limit drug activity to specific body compartments (4).

No potential conflicts of interest were disclosed.