Hematopoietic aging promotes cancer by fueling IL-1⍺-driven emergency myelopoiesis.

Age is a major risk factor for cancer, but how aging impacts tumor control remains unclear. Here, we establish that aging of the immune system, regardless of the age of the stroma and tumor, drives lung cancer progression. Hematopoietic aging enhances emergency myelopoiesis, resulting in the local accumulation of myeloid progenitor-like cells in lung tumors. These cells are a major source of IL-1⍺ that drives the enhanced myeloid response. The age-associated decline of DNMT3A enhances IL-1⍺ production, and disrupting IL-1R1 signaling early during tumor development normalized myelopoiesis and slowed the growth of lung, colonic, and pancreatic tumors. In human tumors, we identified an enrichment for IL-1⍺-expressing monocyte-derived macrophages linked to age, poorer survival, and recurrence, unraveling how aging promotes cancer and offering actionable therapeutic strategies.

Protocol for the development of mRNA lipid nanoparticle vaccines and analysis of immunization efficiency in mice.

Here, we present a protocol for the development of mRNA-loaded lipid nanoparticle (LNP) vaccines for target antigen sequences of interest. We describe key steps required to design and synthesize mRNA constructs, their LNP encapsulation, and mouse immunization. We then detail quality control assays to determine RNA purity, guidelines to measure RNA immunogenicity using in vitro reporter systems, and a technique to evaluate antigen-specific T cell responses following immunization.

Cancer cells co-evolve with retrotransposons to mitigate viral mimicry.

Overexpression of repetitive elements is an emerging hallmark of human cancers 1 . Diverse repeats can mimic viruses by replicating within the cancer genome through retrotransposition, or presenting pathogen-associated molecular patterns (PAMPs) to the pattern recognition receptors (PRRs) of the innate immune system 2-5 . Yet, how specific repeats affect tumor evolution and shape the tumor immune microenvironment (TME) in a pro- or anti-tumorigenic manner remains poorly defined. Here, we integrate whole genome and total transcriptome data from a unique autopsy cohort of multiregional samples collected in pancreatic ductal adenocarcinoma (PDAC) patients, into a comprehensive evolutionary analysis. We find that more recently evolved S hort I nterspersed N uclear E lements (SINE), a family of retrotransposable repeats, are more likely to form immunostimulatory double-strand RNAs (dsRNAs). Consequently, younger SINEs are strongly co-regulated with RIG-I like receptor associated type-I interferon genes but anti-correlated with pro-tumorigenic macrophage infiltration. We discover that immunostimulatory SINE expression in tumors is regulated by either L ong I nterspersed N uclear E lements 1 (LINE1/L1) mobility or ADAR1 activity in a TP53 mutation dependent manner. Moreover, L1 retrotransposition activity tracks with tumor evolution and is associated with TP53 mutation status. Altogether, our results suggest pancreatic tumors actively evolve to modulate immunogenic SINE stress and induce pro-tumorigenic inflammation. Our integrative, evolutionary analysis therefore illustrates, for the first time, how dark matter genomic repeats enable tumors to co-evolve with the TME by actively regulating viral mimicry to their selective advantage.

The Preprint Club: A blueprint for community-based peer review: A blueprint for community-based peer review.

Cross-institutional journal clubs focused on preprints are a new approach to community-based peer review and allow ERCs to gain experience.

Dark genome, bright ideas: Recent approaches to harness transposable elements in immunotherapies.

Transposable elements (TEs), which make up almost half of the human genome, often display altered expression in cancers. Here, we review recent progress in elucidating the role of TEs as mediators of immune responses in cancer and discuss how novel therapeutic strategies can harness TE immunogenicity for cancer immunotherapy.

Y RNAs are conserved endogenous RIG-I ligands across RNA virus infection and are targeted by HIV-1.

Pattern recognition receptors (PRRs) protect against microbial invasion by detecting specific molecular patterns found in pathogens and initiating an immune response. Although microbial-derived PRR ligands have been extensively characterized, the contribution and relevance of endogenous ligands to PRR activation remains overlooked. Here, we characterize the landscape of endogenous ligands that engage RIG-I-like receptors (RLRs) upon infection by different RNA viruses. In each infection, several RNAs transcribed by RNA polymerase III (Pol3) specifically engaged RLRs, particularly the family of Y RNAs. Sensing of Y RNAs was dependent on their mimicking of viral secondary structure and their 5'-triphosphate extremity. Further, we found that HIV-1 triggered a VPR-dependent downregulation of RNA triphosphatase DUSP11 in vitro and in vivo, inducing a transcriptome-wide change of cellular RNA 5'-triphosphorylation that licenses Y RNA immunogenicity. Overall, our work uncovers the contribution of endogenous RNAs to antiviral immunity and demonstrates the importance of this pathway in HIV-1 infection.

Highlights from a year in a pandemic.

COVID-19 has emerged as one of the worst pandemics in recent history and has exposed the weaknesses of healthcare systems worldwide. Here, we reflect on the lessons learned from a year in a pandemic. We discuss the extraordinary scientific advances made in our understanding of a new disease, the failed and successful attempts to halt its progression, and the impact of the pandemic on the scientific discourse within the global community.

Immunology of COVID-19: Current State of the Science.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this Review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.

Global Cancer Transcriptome Quantifies Repeat Element Polarization between Immunotherapy Responsive and T Cell Suppressive Classes.

It has been posited that anti-tumoral innate activation is driven by derepression of endogenous repeats. We compared RNA sequencing protocols to assess repeat transcriptomes in The Cancer Genome Atlas (TCGA). Although poly(A) selection efficiently detects coding genes, most non-coding genes, and limited subsets of repeats, it fails to capture overall repeat expression and co-expression. Alternatively, total RNA expression reveals distinct repeat co-expression subgroups and delivers greater dynamic changes, implying they may serve as better biomarkers of clinical outcomes. We show that endogenous retrovirus expression predicts immunotherapy response better than conventional immune signatures in one cohort yet is not predictive in another. Moreover, we find that global repeat derepression, including the HSATII satellite repeat, correlates with an immunosuppressive phenotype in colorectal and pancreatic tumors and validate in situ. In conclusion, we stress the importance of analyzing the full spectrum of repeat transcription to decode their role in tumor immunity.

Measuring Innate Immune Responses to Bacterial Viability.

The innate immune system directly senses microbial viability via the detection of a special class of viability-associated pathogen-associated molecular patterns (vita-PAMPs), such as prokaryotic messenger RNA. In the case of Gram-negative bacteria, detection of bacterial viability by phagocytes leads to a unique activation of inflammasome and type I interferon pathways, resulting in a robust pro-inflammatory innate response and a vigorous adaptive immune response. This protocol describes the methods required to study activation of both inflammasome and type I interferon pathways after stimulation of mouse bone marrow-derived macrophages with live or killed Gram-negative and Gram-positive bacteria. It covers the generation and handling of bone marrow-derived macrophages, the culture and killing of bacteria, the preparation of bacterial messenger RNA, and the stimulation of macrophages with live or killed bacteria. Lastly, this protocol describes the techniques employed to measure the hallmarks of inflammasome (secretion of interleukin-1ß) and type I interferon (activation of TBK1, IRF3 and secretion of type I interferon) pathways.

Sequence-Specific Sensing of Nucleic Acids.

Innate immune cells are endowed with many nucleic acid receptors, but the role of sequence in the detection of foreign organisms remains unclear. Can sequence patterns influence recognition? In addition, how can we infer those patterns from sequence data? Here, we detail recent computational and experimental evidence associated with sequence-specific sensing. We review the mechanisms underlying the detection and discrimination of foreign sequences from self. We also describe quantitative approaches used to infer the stimulatory capacity of a given pathogen nucleic acid species, and the influence of sequence-specific sensing on host-pathogen coevolution, including endogenous sequences of foreign origin. Finally, we speculate how further studies of sequence-specific sensing will be useful to improve vaccine design, gene therapy and cancer treatment.