TMIC-72. Glioma-associated myeloid cells promote B cell inhibition

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Abstract Glioblastoma (GBM) is the deadliest primary brain tumor, characterized by immunosuppression, low infiltration of lymphocytes, and lack of response to immune checkpoint blockade (ICB) therapies. In other solid tumors, the presence of functional B cells is predictive of response to ICB. However, in GBM, although B cells are antigen-experienced, they do not differentiate to functional plasma cells. B cell activation is opposed by inhibitory signaling, especially mediated through the key inhibitory receptor CD22, which must be halted for differentiation to proceed. We hypothesized that GBM-infiltrating B cells are functionally arrested via CD22 and the immunosuppressive GBM microenvironment, which is characterized by high numbers of tumor-associated myeloid cells (TAMs). Using patient GBM samples and GBM single-cell RNA sequencing data, we showed that TAMs such as microglia strongly express the CD22 ligand α2,6 sialic acid and the α2,6 sialic acid-synthesizing enzyme ST6GAL1. We created an in vitro model of TAMs by treating murine bone-marrow-derived myeloid cells (BMDMs) with supernatant from the murine glioma cell line CT2A. Tumor cell supernatant doubled the expression of α2,6 sialic acid on the TAMs compared to BMDMs, driven by increased expression of St6gal1, showing that secreted factors from tumor cells may remodel TAMs toward a more immunosuppressive state. To elucidate the direct impact of myeloid cells on B cells, we cocultured B cells with TAMs or the microglial cell line BV2. B cells cocultured with TAMs and BV2 cells showed increased phosphorylation of repressive signaling molecules downstream of CD22, including p-SHP-2 and p-SHIP1. This study suggests that myeloid cells are reprogrammed in the context of the tumor microenvironment to become more suppressive to B cells. In future work, we aim to develop a therapeutic targeting α2,6 sialic acid on TAMs in vivo to restore B cell function.

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