In this issue of Neuro-Oncology, Friedrich et al.1 from the German Cancer Research Center in Heidelberg, Germany, investigate the importance of conventional dendritic cell (cDC) subsets to anti-tumor immunity and compare their phenotypic and functional differences between IDH-mutant and IDH wild type tumors in preclinical models. The importance of these cDC in anti-tumor immunity have been proven in other extracranial tumors in recent years.2 cDC1 are now known to be critical for the cross-presentation of tumor antigens, and loss of this unique cDC population is directly related to substantial deficiency for mice to reject transplantable tumors.3,4 Little is known about the immunological relevance of these cDC populations in gliomas. Although, recent findings from the single cell RNA-seq of recurrent glioblastoma (GBM) patients treated with neoadjuvant Programmed Death 1 (PD-1) immune checkpoint blockade suggests that the local activation of T cells within the tumor microenvironment activates a chemokine axis by which cDC are recruited into the tumors of these patients, highlighting the central role cDC play.5
Tumors can also influence the function of cDC by creating an immunosuppressive milieu. The main findings of this study are that DCs are present in both human and murine models of glioma, and the transcriptomes and protein identification of cell types are different between the isocitrate dehydrogenase (IDH) mutant and IDH wild-type gliomas examined. Some of the data comes from a re-analysis of recently published findings reported in Nature Cancer.6 Friedrich et al., demonstrate how the presence of 2-hydroxy glutarate (2-HG) in genetically engineered IDH-mutant gliomas impairs the differentiation of monocytes into cDC, which takes place more efficiently in IDH-wt tumors. This differentiation block concurs with decreased antigen-presenting ability and differences in microenvironmental cytokine milieu (increased IL-6, decreased IL-4, and IL-13) of IDH mutant gliomas, and ultimately reduces the proliferation and recruitment of antigen-specific T cells relative to IDH-wt. Such data complements other recently published work on how 2-HG directly impairs the function and activity of T cells and underscores the concept that very separate mechanisms of immunosuppression are at work in IDH-mut vs IDH-wt tumors.7,8
This article contributes to the emerging literature on the importance of cDC for effective anti-tumor immunity, and further suggests that distinct subtypes of glioma and/or oncogenic metabolites may interfere in this process. However, there are limitations to the work; it is known that engineered IDH mutations in established tumor cell lines do not recapitulate all of the true biology of these distinct tumors. In addition, it is not known mechanistically how IDH mutant gliomas impair the differentiation of these cDC populations, and despite these differences in cDCs, both IDH-mut and IDH-wt tumors have proven refractory to immunotherapeutics. As such, other mechanisms may play a large role in governing the anti-tumor immune response. Thus, we must be cautious in our interpretation of these findings. However, these findings are an important step in our understanding of the tumor microenvironment in these tumors.
Contributor Information
Robert M Prins, Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Richard G Everson, Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Declaration
This commentary is the sole product of these authors, and no third party had input or gave support to its writing.
Funding
This work was supported by National Institutes of Health, National Cancer Institute SPORE in Brain Cancer (2P50CA211015-06).
References
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