The following articles have been recommended for further reading in the field of cancer immunotherapy by JITC's Oncolytic and Local Immunotherapy Section Editor, Howard Kaufman, MD, FACS.
“Structural cells are key regulators of organ-specific immune responses” by Thomas Krausgruber et al
Structural cells are generally though to support immune defense solely through their barrier functions or roles as connective tissue, however emerging research is revealing basic mechanisms of pathogen defense are not restricted solely to hematopoietic cells. To develop a high-resolution atlas of immune potential in mouse structural cells, Thomas Krausgruber and colleagues performed gene expression profiling with low-input RNAseq, chromatin accessibility profiling by ATACseq, and ChIP-mentation with an antibody against the promoter- and enhancer-link histone mark H3K4me2 on endothelium, epithelium and fibroblasts from 12 organs: brain, cecum, heart, kidney, large intestine, liver, lung, lymph node, skin, small intestine, spleen and thymus. Extensive cell-type- and organ-specific chromatin regulation was observed at immune gene loci in structural cells, although a subset of crucial immune genes showed high chromatin accessibility across most samples. Scanning for genes with low expression but high promoter accessibility revealed 1,665 genes with unrealized epigenetic potential, of which 335 were annotated with one or more immunological terms. Characterization of structural cells 8 days after lymphocytic choriomeningitis virus (LCMV) infection revealed that the transcriptional response among epithelium, endothelium and fibroblasts was globally more similar within the same organ than between cell types across organs. Genes with unrealized epigenetic potential were overrepresented among LCMV-induced genes, especially in liver, lung and spleen. Depending on the cell- and organ-type examined, treatment with recombinant cytokines explained variable proportions of the LCMV-induced transcriptional changes. For example, in spleen endothelium, IFNγ and IL-6 explained the majority of altered gene expression after LCMV infection. By contrast, in liver fibroblasts, little overlap was seen between the transcriptional responses to cytokines and LCMV infection. The findings lay the groundwork for a new concept of ‘structural immunity,’ intrinsic to non-hematopoietic cell populations and specific to different organs in the mammalian body. This work has important implications for tumor immunotherapy by highlighting the potential role of tissue-specific stromal cells in regulating immune responses in the tumor microenvironment. In addition, the data suggest new targets for immunotherapy drug development and suggest that local therapy may have different impacts on tumor immunity depending on the tissue targeted.
“Early type I IFN blockade improves the efficacy of viral vaccines” by Nicole Palacio et al
A delicate balance exists between efficient early viral clearance by innate defense mechanisms and the establishment of long-term immunological memory by the adaptive immune system. Hypothesizing that transient blockade of type I interferon (IFN-I) signaling could increase viral antigen presentation, Nicole Palacio and colleagues administered a single dose of IFN-I receptor-blocking antibody to mice concomitantly with several different viruses and vaccines. Short-term IFN-I blockade administered along with Zika virus infection led to 36-fold improved CD8+ T cell responses and 82-fold improved antibody responses. Blockade of IFN-I increased the immunogenicity of yellow fever, rhabdovirus and arenavirus vaccines, and facilitated germinal center B cell responses in the context of LCMV-HIV vaccination, indicating improved antibody diversification. Although complete viral clearance was ultimately observed by day 7 in all mice, short-term IFN-I blockade led to a sharp increase in viral titers 72 hours after infection. Dendritic cells from mice that received IFN-I blockade had higher levels of MHC-I molecules presenting cognate antigen and expressed higher levels of costimulatory molecules relative to controls, and experiments with one-hit viruses demonstrated that the establishment of secondary foci of infection is necessary for the adjuvant effect of IFN-I blockade. In six different challenge models, including Zika virus, coronaviruses, and vaccines for Listeria monocytogenes, the administration of IFN-I blockade along with the initial inoculum improved immune protection—leading to sterilizing immunity after reinfection. Given that IFN-I blockers have shown acceptable safety profiles when used in humans for inflammatory diseases, the findings provide intriguing insights for future rational vaccine design. These insights have implications for cancer immunotherapy, perhaps most obviously in optimizing oncolytic virus therapy, and further pre-clinical research with commonly used oncolytic viruses can be anticipated.
“Hybrid gene origination creates human-virus chimeric proteins during infection” by Jessica Sook Yuin Ho et al
Segmented negative stand RNA viruses, which include the families Arenaviridae, Peribunyaviridae, and Orthomyxoviridae, prime viral mRNA synthesis using short 5’methyl-7-guanosine capped RNA sequences cleaved from host RNA polymerase II transcripts in a process known as “cap-snatching.” To determine if start codons in snatched caps could lead to the generation of novel chimeric proteins, Jessica Sook Yuin Ho et al determined the abundance of uAUGs in cap-snatched host sequences archived in a Decap and 5’ end sequencing (DEFEND-seq) dataset for influenza A virus. Host-derived sequences with AUG codons were present at similar ratios in all eight genome segments of the virus in all three reading frames, totaling roughly 12% of all cap-snatched sequences. Furthermore, the 5’ untranslated regions (UTRs) lacked upstream stop codons in-frame with the major open reading frames (ORF) for five of the eight genome segments, and upstream stop codons out of frame with the major ORF were absent from six of the eight genome segments. In silico, novel ORFs overlapping with canonical viral genes read in different frames (overprinted) were detected, with lengths ranging from more than 40 to nearly 80 residues, and N-terminal extensions of the major ORFs were found with lengths of 8–21 amino acids. Ribosomal profiling of influenza A virus infected cells in the presence of harringtonine, which blocks elongation of de novo assembled 80S initiation complexes, mapped reads to alternative initiation codons in cap-snatched 5’ UTRs totaling as many as 5% to 20% of the reads mapping to canonical start codons. Mass spectrometry analyses of lysates from infected cells identified two distinct peptides derived from overprinted ORFs in the PB1 and PB2 segments, which were named PB1-UFO and PB2-UFO, respectively, for ‘‘Upstream Frankenstein ORF,’’ as well as a UTR-encoded N-terminal extension of NP. Peptides derived from the PB1-UFO protein were also detected in three previously published proteomic datasets of IAV infection. Mouse dendritic cells presented epitopes of the overprinted peptides, leading to T cell activation. Intriguingly, virulence was altered when stop codons were inserted into 5’ UTRs, with viruses unable to produce the N-terminal extension of NP becoming less virulent and viruses lacking the ability to produce PB1-UFOD displaying increased virulence, although only at high infectious doses. Start codons with read-through potential were also detected in influenza B virus as well as Lassa virus. The findings not only reveal a new mechanism for the production of viral proteins that shape interactions with the host, but raise provocative questions about the definition of a gene. This manuscript suggests a new mechanism for generating neoantigens within neoplastic cells and provides a new paradigm for how cancer-associated viruses de nove and oncolytic viruses therapeutically might mediate antigen-specific immunity.
“Interferon-independent activities of mammalian STING mediate antiviral response and tumor immune evasion” by Jianjun Wu et al
Interferon (IFN) signaling is widely believed to be the dominant, if not the only, mechanism by which STING controls viral infections and cancer in mammals, yet many species across the tree of life harbor forms of the protein that lack the functional motif required for the IFN response. Taking advantage of the fact that phosphorylation of a single serine residue is necessary for IFN signaling (residue S365 in mice and S366 in humans), Jianjun Wu et al dissected the IFN-independent activities of STING for tumor control and antiviral defense. In both bone marrow-derived macrophages (BMDMs) and T cells from mice homozygous for the S365A mutation, IFN-simulated gene (ISG) expression was completely eliminated while NF-kB signaling was unaffected. Transcriptomic analyses of cells isolated from wild type and S365A mutant mice revealed that the majority of differentially expressed genes after treatment with the STING agonist DMXAA in BMDMs were IFN-dependent, whereas the opposite phenomenon was seen in T cells. STING activation was associated with significant reduction in expression of genes associated with DNA methylation, as well as Th17 signaling, Th1 signaling, NF-kB signaling, nuclear factor of activated T cells (NFAT) signaling, the unfolded protein response, IL-2 pathways, and cell death. Surprisingly, mice with S365A-mutant STING controlled herpes simplex virus 1 (HSV-1) infection, while STING-knockout mice rapidly succumbed. Human BMDM harboring S366A-mutant STING were more resistant to HSV-1 infection compared to full knockout cell lines, whereas susceptibility to vaccinia virus was identical. In adoptive transfer experiments, STING knockout T cells controlled tumor growth significantly better than wild type or S365A mutant T cells for both B16 melanoma and MC38 colon cancer models. Significantly more cell death was observed in intratumoral CD8+ lymphocytes for the S365A and wild type T cells compared to full STING knockout T cells. Lower numbers of tumor-infiltrating T cells were observed inside MC38 tumors in STING mutant mice (both S365A and full knockout) compared to wild-type mice. However, significantly reduced T cell death was observed in tumors implanted in STING knockout mice compared to wild-type mice and S365A mutant mice. The findings reveal interferon-independent activities of STING that are important for antiviral defense against some viruses as well as tumor control. This paper suggests an important alternative pathway through which STING may mediate anti-viral and anti-tumor immunity and may explain some of the contradictory findings related to the role of type I interferons in tumor immunotherapy. The data further strengthens the link between innate immune signaling and other cell signaling pathways that serve to induce anti-tumor immunity by transformed cells.
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