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. 2017 Sep 1;64(CN_suppl_1):165-176.
doi: 10.1093/neuros/nyx321.

Targeting Neoantigens in Glioblastoma: An Overview of Cancer Immunogenomics and Translational Implications

Tanner M Johanns  1   2 , Jay A Bowman-Kirigin  3   4 , Connor Liu  3   4 , Gavin P Dunn  2   4   5
Affiliations

Targeting Neoantigens in Glioblastoma: An Overview of Cancer Immunogenomics and Translational Implications

Tanner M Johanns et al. Neurosurgery. .
No abstract available

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Figures

FIGURE 1.
FIGURE 1.
Routes of CNS-based tumor antigen drainage to regional lymph nodes. Tumor-derived antigens can reach draining cervical lymph nodes in several ways. Antigen that gains access to the CSF either by direct extension of the tumor, breakdown of the BBB, cellular trafficking by APC, or through glymphatic exchange can enter the lymphatic system by traversing the cribiform plate into the nasal mucosa (1) or through meningeal lymphatics of the dura (3). Alternatively, acellular antigen can enter the wall of intraparenchymal capillaries and arteries to migrate retrograde toward local lymph nodes (2). BBB, blood–brain barrier; CSF, cerebrospinal fluid; GBM, glioblastoma; ISF, interstitial fluid. Adapted from Engelhardtet al.
FIGURE 2.
FIGURE 2.
Proposed model of leukocyte recruitment due to altered BBB integrity in GBM. A, Under normal conditions, the dual layers of the BBB is maintained through tight junctions between capillary endothelial cells and the glia limitans, which is comprised of astrocytic end-foot processes. In the postcapillary venules, these 2 layers separate creating a perivascular (Virchow-Robin) space, which contains resident macrophages. B, In the context of GBM or inflammation, the BBB is disrupted. The glia limitans loses polarity due to altered expression of AQP4 in the astrocytic end-foot processes leading to expansion of the perivascular space and communication with the underlying parenchyma (1). The capillary tight junctions are disrupted due to reduced expression of claudin-3, which permits exchange of solutes, antigens, and chemokines/cytokines (2). It also allows circulating leukocytes, such as neutrophils, monocytes, and T cells, to gain access to the perivascular space where they interact with APC that present tumor antigen from the parenchyma (3). AQP4, aquaporin 4 molecule; BBB, blood–brain barrier; GBM, glioblastoma.
FIGURE 3.
FIGURE 3.
Schematic representation of cancer immunogenomics workflow for neoantigen discovery. Normal reference tissue (ie, PBMC) and tumor tissue is obtained and undergoes DNA whole exome and RNA sequencing to identify somatic, nonsynonymous mutations. Tumor-specific mutations are then filtered using computational software to prioritize neoantigens based on expression, predicted patient-specific HLA binding affinity, and likelihood of endogenous proteosomal processing. Peptides corresponding to candidate high-quality neoantigens are then manufactured and administered back to the patient as a personalized vaccine. PBMC, peripheral blood mononuclear cell.
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