Poliovirus Receptor (CD155) Expression in Pediatric Brain Tumors Mediates Oncolysis of Medulloblastoma and Pleomorphic Xanthoastrocytoma

Abstract

Poliovirus oncolytic immunotherapy is a putatively novel approach to treat pediatric brain tumors. This work sought to determine expression of the poliovirus receptor (PVR), CD155, in low-grade and malignant pediatric brain tumors and its ability to infect, propagate, and inhibit cell proliferation. CD155 expression in pleomorphic xanthoastrocytoma (PXA), medulloblastoma, atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, and anaplastic ependymoma specimens was assessed. The ability of the polio: rhinovirus recombinant, PVSRIPO, to infect PXA (645 [BRAF V600E mutation], 2363) and medulloblastoma (D283, D341) cells were determined by viral propagation measurement and cell proliferation. PVR mRNA expression was evaluated in 763 medulloblastoma and 1231 normal brain samples. CD155 was expressed in all 12 patient specimens and in PXA and medulloblastoma cell lines. One-step growth curves at a multiplicity of infection of 10 demonstrated productive infection and peak plaque formation units at 5-10 hours. PVSRIPO infection significantly decreased cellular proliferation in 2363, 645, and D341 cell lines at 48 hours (p < 0.05) and resulted in cell death. PVR expression was highest in medulloblastoma subtypes Group 3c, WNTa, and WNTb (p < 0.001). This proof-of-concept in vitro study demonstrates that PVSRIPO is capable of infecting, propagating, prohibiting cell proliferation, and killing PXA and Group 3 medulloblastoma.

CD155 immunoregulation as a target for natural killer cell immunotherapy in glioblastoma

“…Upregulation of both membrane-bound and soluble CD155 in U87MG glioblastoma cells was subsequently reported by other groups [25]. Thompson et al showed that a variety of low-grade and malignant pediatric brain tumors also overexpress CD155 and that targeting of CD155 on these tumors using an oncolytic virus could inhibit cellular proliferation of GBM [26]. Further confirming these findings have been large-scale IHC studies which have indicated the prevalence of CD155 in GBM and other gliomas [11,27,28].…”

Overexpression of an Immune Checkpoint (CD155) in Breast Cancer Associated with Prognostic Significance and Exhausted Tumor-Infiltrating Lymphocytes: A Cohort Study

“…CD155 is the molecule expressing during embryonic period, which barely expresses in normal tissues, but reexpresses in malignant tissues [9,[11][12][13]22]. Moreover, soluble isoforms of CD155 have been found to be highly expressed in the sera of patients with lung, gastrointestinal, breast, and gynaecologic cancers than that of in healthy volunteers [23].…”

Targeting PVR (CD155) and its receptors in anti-tumor therapy

“…106 This specificity is likely due to the IRES-binding protein DRBP76 that prevents ribosome binding and subsequent viral protein synthesis and replication in neuronal cells, while in tumor cells, the absence of this protein in the cytoplasm means that the IRES is not bound, resulting in the viral replication and lytic cycle. [107][108][109][110] Numerous studies have confirmed the inability of this recombinant poliovirus to kill neuronal cells while retaining the ability to kill tumor cells, 2,106,[111][112][113][114] and the safety of PVSRIPO has also been confirmed in preclinical, human PVR transgenic mouse models. 115 However, as mentioned above, the selective replication of oncolytic viruses in tumor cells is not the sole requirement for their efficacy and therapeutic applications.…”