Biology subjects

Bigner, D. D.

Publications and source records attributed to Bigner, D. D..

3 recordsLinked to original sources

bioRxiv2022

Polio Virotherapy of Malignant Glioma Engages the Tumor Myeloid Infiltrate and Induces Diffuse Microglia Activation

Malignant gliomas commandeer abundant inflammatory infiltrates with glioma-associated macrophages and microglia (GAMM) actively promoting tumor progression. Like all cells in the mononuclear phagocytic system, macrophages and microglia constitutively express the poliovirus receptor, CD155. Besides myeloid cells, CD155 is widely upregulated ectopically in the neoplastic compartment of malignant gliomas (and solid cancers in general). Intratumor treatment with the highly attenuated rhino:poliovirus chimera, PVSRIPO, yielded long-term survival with durable radiographic responses in patients with recurrent glioblastoma (Desjardins et al. New England Journal of Medicine, 2018). Here, we studied mechanisms of PVSRIPO immunotherapy in mouse brain tumor models to decipher contributions of myeloid vs. malignant cells to antitumor efficacy. PVSRIPO treatment caused intense engagement of the GAMM infiltrate associated with substantial, but transient tumor regression. This was accompanied by diffuse microglia activation and proliferation in the normal central nervous system (CNS) surrounding the tumor, extending to the ipsilateral and even the contralateral hemispheres. PVSRIPO-instigated microglia activation occurred against a backdrop of sustained innate antiviral inflammation, associated with induction of the PD-L1 immune checkpoint on GAMM. Combining PVSRIPO with PD1/PD-L1 blockade led to durable remissions. Our work implicates GAMM as active drivers of PVSRIPO-induced antitumor inflammation and reveals profound and widespread neuroinflammatory activation of the CNS-resident myeloid compartment by PVSRIPO.

cancer biology↗

bioRxiv2022

Intratumoral Recall of Childhood Vaccine-Specific CD4+ T cells Coordinates Type I and II Antitumor Immunity

BackgroundCD4+ T cells are key contributors to cancer immune surveillance. However, means to effectively harness CD4+ T cell help for cancer immunotherapy are lacking, and antitumor mechanisms of CD4+ T cells remain crudely defined. MethodsThe impact of polio immunization on polio virotherapy was tested in syngeneic murine melanoma and breast cancer models. Antitumor effects of polio and tetanus toxoid antigens were assessed in polio and tetanus immunized mice. T and B cell knockout mice, CD4+ T cell adoptive transfer, and eosinophil depletion demonstrated cell-type specific contributions to the antitumor efficacy of polio recall. Phenotyping of adoptively transferred OT-I (OVA-specific) T cells in B16-OVA tumor bearing mice, as well as adoptive transfer of T cells to naive tumor-bearing recipients, measured the impact of intratumor polio/tetanus recall on antitumor T cell immunity. Pan-cancer human transcriptome data sets were queried to test associations between eosinophils and Tregs; cytokine profiles of polio and tetanus recall were defined in human peripheral blood of healthy donors and cancer patients; CD40L blockade was used to determine dependency of recall antigen therapy on CD40:CD40L signaling. ResultsPrior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth in a manner complemented by pattern recognition receptor agonist therapy and PD1 blockade. Intratumor recall antigens augmented antitumor T cell function, and caused marked tumor infiltration of type 2 innate lymphoid cells (ILC2s) and eosinophils, coinciding with decreased proportions of intratumor Tregs. Antitumor effects of recall antigens were mediated by CD4+ T cells, independent of CD40L signaling, and were dependent on both eosinophils and CD8+ T cells. Human PBMCs mounted diverse cytokine/chemokine responses, which were not impaired in patients with advanced cancer, and an inverse relationship between eosinophil and Treg signatures was observed across TCGA cancer types. ConclusionThis work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4+ T cell help for antitumor CD8+ T cells, and implicates eosinophils as antitumor effectors of CD4+ T cells.

immunology↗

bioRxiv2021

Distribution and vulnerability of transcriptional outputs across the genome in Myc-amplified medulloblastoma cells

Myc plays a central role in tumorigenesis by orchestrating the expression of genes essential to numerous cellular processes1-4. While it is well established that Myc functions by binding to its target genes to regulate their transcription5, the distribution of the transcriptional output across the human genome in Myc-amplified cancer cells, and the susceptibility of such transcriptional outputs to therapeutic interferences remain to be fully elucidated. Here, we analyze the distribution of transcriptional outputs in Myc-amplified medulloblastoma (MB) cells by profiling nascent total RNAs within a temporal context. This profiling reveals that a major portion of transcriptional action in these cells was directed at the genes fundamental to cellular infrastructure, including rRNAs and particularly those in the mitochondrial genome (mtDNA). Notably, even when Myc protein was depleted by as much as 80%, the impact on transcriptional outputs across the genome was limited, with notable reduction mostly only in genes involved in ribosomal biosynthesis, genes residing in mtDNA or encoding mitochondria-localized proteins, and those encoding histones. In contrast to the limited direct impact of Myc depletion, we found that the global transcriptional outputs were highly dependent on the activity of Inosine Monophosphate Dehydrogenases (IMPDHs), rate limiting enzymes for de novo guanine nucleotide synthesis and whose expression in tumor cells was positively correlated with Myc expression. Blockage of IMPDHs attenuated the global transcriptional outputs with a particularly strong inhibitory effect on infrastructure genes, which was accompanied by the abrogation of MB cells proliferation in vitro and in vivo. Together, our findings reveal a real time action of Myc as a transcriptional factor in tumor cells, provide new insight into the pathogenic mechanism underlying Myc-driven tumorigenesis, and support IMPDHs as a therapeutic vulnerability in cancer cells empowered by a high level of Myc oncoprotein.

cancer biology↗