Abstract
Diffuse intrinsic pontine gliomas (DIPGs) are the most aggressive tumors of the central nervous system in children. Median survival of patients is less than one year post-diagnosis. Radiotherapy remains the only standard treatment but is rarely curative. Immunotherapy is an emerging and promising treatment strategy for children with DIPG. However, general immunotherapy has not lived up to its promise to treat many cancers, including DIPGs, in part due to incomplete understanding of the barriers posed by the tumor microenvironment. We therefore evaluated the immune cell infiltration in a syngeneic mouse model of DIPG and in DIPG tumors collected from patients. We evaluated the expression profiles of T lymphocytes and myeloid cell markers in a cohort of 28 DIPG tumors compared to matched normal tissue specimens. Our data indicate that the expression of MHC I components in DIPG tumors is similar to that of matched normal tissue. Moreover, the well-known immune checkpoint, PD-L1, was not overexpressed in DIPG tumors. Using immunohistochemistry, we demonstrated only rare infiltration of lymphocytes but high enrichment of myeloid cells in tumor tissue. We found similar results in a syngeneic mouse model of DIPG. Collectively, our results indicate that DIPG tumors harbor rare lymphocytes and are enriched in myeloid cells. Recent studies have demonstrated that DNA methyltransferase inhibitors prime some tumors for more effective checkpoint blockade by activating expression of human endogenous retroviruses and sparking a T-cell mediated immune response through a process called “viral mimicry.” We tested the effect of decitabine in a syngeneic mouse model of DIPG. Decitabine reduced the tumor growth kinetics compared to vehicle but was unable to induce the recruitment of lymphoid cells in DIPG tumors. Importantly, we observed a noticeable reduction in the myeloid component of the DIPG microenvironment suggesting a possible role of myeloid cells in tumor growth and progression.
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