Lessons in antiviral immunity Hope, Jennifer L; Bradley, Linda M
Science,
2021-Jan-29, 2021-01-29, 20210129, Volume:
371, Issue:
6528
Journal Article
Peer reviewed
Open access
Immune responses to SARS-CoV-2 reveal regulation and dynamics of lymphocytes
The adaptive branch of the immune system can kill virally infected cells and generate protective immune memory, which is ...the basis of vaccination strategies. Both T cell and B cell responses are important in controlling viruses and the development of immunity. However, the COVID-19 pandemic is revealing widely varying immune responses and diverse clinical outcomes with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, raising questions about how antiviral responses are orchestrated, factors that influence the longevity of immunological memory, and approaches that mediate robust protection from viral infections.
Chronic viruses and cancers thwart immune responses in humans by inducing T cell dysfunction. Using a murine chronic virus that models human infections, we investigated the function of the adhesion ...molecule, P-selectin glycoprotein ligand-1 (PSGL-1), that is upregulated on responding T cells. PSGL-1-deficient mice cleared the virus due to increased intrinsic survival of multifunctional effector T cells that had downregulated PD-1 as well as other inhibitory receptors. Notably, this response resulted in CD4+-T-cell-dependent immunopathology. Mechanistically, PSGL-1 ligation on exhausted CD8+ T cells inhibited T cell receptor (TCR) and interleukin-2 (IL-2) signaling and upregulated PD-1, leading to diminished survival with TCR stimulation. In models of melanoma cancer in which T cell dysfunction occurs, PSGL-1 deficiency led to PD-1 downregulation, improved T cell responses, and tumor control. Thus, PSGL-1 plays a fundamental role in balancing viral control and immunopathology and also functions to regulate T cell responses in the tumor microenvironment.
Display omitted
•T cell survival was increased in Selplg−/− mice after chronic virus infection•Multi-functional anti-viral T cells in Selplg−/− mice promoted viral control•Ligating PSGL-1 on exhausted CD8+ T cells silenced TCR signals•PSGL-1-deficiency enhanced T cell anti-tumor immunity to melanoma
PSGL-1 is an adhesion molecule known to be important for migration of hematopoietic cells. Bradley and colleagues show that PSGL-1 on T cells dampens TCR signals, limits survival of effector T cells, and promotes immune inhibitory receptor expression, thereby supporting establishment of exhaustion in viral and tumor models.
Growing evidence supports the importance of gut microbiota in the control of tumor growth and response to therapy. Here, we select prebiotics that can enrich bacterial taxa that promote anti-tumor ...immunity. Addition of the prebiotics inulin or mucin to the diet of C57BL/6 mice induces anti-tumor immune responses and inhibition of BRAF mutant melanoma growth in a subcutaneously implanted syngeneic mouse model. Mucin fails to inhibit tumor growth in germ-free mice, indicating that the gut microbiota is required for the activation of the anti-tumor immune response. Inulin and mucin drive distinct changes in the microbiota, as inulin, but not mucin, limits tumor growth in syngeneic mouse models of colon cancer and NRAS mutant melanoma and enhances the efficacy of a MEK inhibitor against melanoma while delaying the emergence of drug resistance. We highlight the importance of gut microbiota in anti-tumor immunity and the potential therapeutic role for prebiotics in this process.
Display omitted
•Mucin and inulin, prebiotics, inhibit melanoma growth in syngeneic mouse models•Changes in gut microbiota taxa by these prebiotics induce anti-tumor immunity•Inulin attenuates melanoma resistance to MEKi in a mouse melanoma model•Inulin and mucin elicit distinct microbiota changes and an additive effect in select models
Li et al. show that the gut microbiota effect on anti-tumor immunity is affected by inulin or mucin, prebiotics that inhibit melanoma and colon cancer growth in syngeneic models and attenuate melanoma resistance to MEKi. These studies highlight a potential therapeutic role for prebiotics in shaping the microbiota composition to promote anti-tumor immunity.
Repetitive elements (REs) compose ∼50% of the human genome and are normally transcriptionally silenced, although the mechanism has remained elusive. Through an RNAi screen, we identified FBXO44 as an ...essential repressor of REs in cancer cells. FBXO44 bound H3K9me3-modified nucleosomes at the replication fork and recruited SUV39H1, CRL4, and Mi-2/NuRD to transcriptionally silence REs post-DNA replication. FBXO44/SUV39H1 inhibition reactivated REs, leading to DNA replication stress and stimulation of MAVS/STING antiviral pathways and interferon (IFN) signaling in cancer cells to promote decreased tumorigenicity, increased immunogenicity, and enhanced immunotherapy response. FBXO44 expression inversely correlated with replication stress, antiviral pathways, IFN signaling, and cytotoxic T cell infiltration in human cancers, while a FBXO44-immune gene signature correlated with improved immunotherapy response in cancer patients. FBXO44/SUV39H1 were dispensable in normal cells. Collectively, FBXO44/SUV39H1 are crucial repressors of RE transcription, and their inhibition selectively induces DNA replication stress and viral mimicry in cancer cells.
Display omitted
•FBXO44 promotes H3K9me3-mediated repetitive element silencing in cancer cells•FBXO44 recruits SUV39H1, CRL4, and Mi-2/NuRD at the replication fork•Targeting FBXO44 stimulates antiviral pathways and replication stress in cancer cells•FBXO44/SUV39H1 inhibition overcomes resistance to immune checkpoint blockade therapy
Targeting FBXO44, which regulates the transcriptional silencing of repetitive elements in the human cancer genome, promotes antiviral signaling and decreases tumorigenesis as well as overcomes resistance to immune checkpoint blockade.
Abstract
Objectives
We assessed the interobserver and interantibody reproducibility of HER2 immunohistochemical scoring in an enriched HER2-low–expressing breast cancer cohort.
Methods
A total of 114 ...breast cancer specimens were stained by HercepTest (Agilent Dako) and PATHWAY anti-HER2 (4B5) (Ventana) antibody assays and scored by 6 breast pathologists independently using current HER2 guidelines. Level of agreement was evaluated by Cohen κ analysis.
Results
Although the interobserver agreement rate for both antibodies achieved substantial agreement, the average rate of agreement for HercepTest was significantly higher than that for the 4B5 clone (74.3% vs 65.1%; P = .002). The overall interantibody agreement rate between the 2 antibodies was 57.8%. Complete interobserver concordance was achieved in 44.7% of cases by HercepTest and 45.6% of cases by 4B5. Absolute agreement rates increased from HER2 0-1+ cases (78.1% by HercepTest and 72.2% by 4B5; moderate agreement) to 2-3+ cases (91.9% by HercepTest and 86.3% by 4B5; almost perfect agreement).
Conclusions
Our results demonstrated notable interobserver and interantibody variation on evaluating HER2 immunohistochemistry, especially in cases with scores of 0-1+, although the performance was much more improved among breast-specialized pathologists with the awareness of HER2-low concept. More accurate and reproducible methods are needed for selecting patients who may benefit from the newly approved HER2-targeting agent on HER2-low breast cancers.
P-selectin glycoprotein ligand-1 (PSGL-1) has long been studied as an adhesion molecule involved in immune cell trafficking and is recognized as a regulator of many facets of immune responses by ...myeloid cells. PSGL-1 also regulates T cell migration during homeostasis and inflammatory settings. However, recent findings indicate that PSGL-1 can also negatively regulate T cell function. Because T cell differentiation is finely tuned by multiple positive and negative regulatory signals that appropriately scale the magnitude of the immune response, PSGL-1 has emerged as an important checkpoint during this process. We summarize what is known regarding PSGL-1 structure and function and highlight how it may act as an immune checkpoint inhibitor in T cells.
Toca 511 (vocimagene amiretrorepvec) is an investigational nonlytic, retroviral replicating vector (RRV) that delivers a yeast cytosine deaminase, which converts subsequently administered courses of ...the investigational prodrug Toca FC (extended-release 5-fluorocytosine) into the antimetabolite 5-fluorouracil. Forty-five subjects with recurrent or progressive high-grade glioma were treated. The end points of this phase 1, open-label, ascending dose, multicenter trial included safety, efficacy, and molecular profiling; survival was compared to a matching subgroup from an external control. Overall survival for recurrent high-grade glioma was 13.6 months (95% confidence interval, 10.8 to 20.0) and was statistically improved relative to an external control (hazard ratio, 0.45; P = 0.003). Tumor samples from subjects surviving more than 52 weeks after Toca 511 delivery disproportionately displayed a survival-related mRNA expression signature, identifying a potential molecular signature that may correlate with treatment-related survival rather than being prognostic. Toca 511 and Toca FC show excellent tolerability, with RRV persisting in the tumor and RRV control systemically. The favorable assessment of Toca 511 and Toca FC supports confirmation in a randomized phase 2/3 trial (NCT02414165).
Abstract
The chemical senses of taste and smell play a vital role in conveying information about ourselves and our environment. Tastes and smells can warn against danger and also contribute to the ...daily enjoyment of food, friends and family, and our surroundings. Over 12% of the US population is estimated to experience taste and smell (chemosensory) dysfunction. Yet, despite this high prevalence, long-term, effective treatments for these disorders have been largely elusive. Clinical successes in other sensory systems, including hearing and vision, have led to new hope for developments in the treatment of chemosensory disorders. To accelerate cures, we convened the “Identifying Treatments for Taste and Smell Disorders” conference, bringing together basic and translational sensory scientists, health care professionals, and patients to identify gaps in our current understanding of chemosensory dysfunction and next steps in a broad-based research strategy. Their suggestions for high-yield next steps were focused in 3 areas: increasing awareness and research capacity (e.g., patient advocacy), developing and enhancing clinical measures of taste and smell, and supporting new avenues of research into cellular and therapeutic approaches (e.g., developing human chemosensory cell lines, stem cells, and gene therapy approaches). These long-term strategies led to specific suggestions for immediate research priorities that focus on expanding our understanding of specific responses of chemosensory cells and developing valuable assays to identify and document cell development, regeneration, and function. Addressing these high-priority areas should accelerate the development of novel and effective treatments for taste and smell disorders.
•Changes in gut microbiota composition are implicated in disease.•Gut microbiota composition impacts immune system function.•Extrinsic and intrinsic factors govern relative abundance of gut ...microbiota commensals.•Manipulation of gut microbiota could impact anti-tumor immunity.
Numerous independent studies link gut microbiota composition and disease and imply a causal role of select commensal microbes in disease etiology. In the gut, commensal microbiota or pathobionts secrete metabolites that underlie pathological conditions, often impacting proximal tissues and gaining access to the bloodstream. Here we focus on extrinsic and intrinsic factors affecting composition of gut microbiota and their impact on the immune system, as key drivers of anti-tumor immunity. In discussing exciting advances relevant to microbiome-tumor interaction, we note existing knowledge gaps that need to be filled to advance basic and clinical research initiatives.
Whether differences between naive cell-derived primary (1°) and memory cell-derived secondary (2°) CD4 ⁺ T-cell effectors contribute to protective recall responses is unclear. Here, we compare these ...effectors directly after influenza A virus infection. Both develop with similar kinetics, but 2° effectors accumulate in greater number in the infected lung and are the critical component of memory CD4 ⁺ T-cell–mediated protection against influenza A virus, independent of earlier-acting memory-cell helper functions. Phenotypic, functional, and transcriptome analyses indicate that 2° effectors share organ-specific expression patterns with 1° effectors but are more multifunctional, with more multicytokine (IFN-γ ⁺/IL-2 ⁺/TNF ⁺)-producing cells and contain follicular helper T-cell populations not only in the spleen and draining lymph nodes but also in the lung. In addition, they express more CD127 and NKG2A but less ICOS and Lag-3 than 1° effectors and express higher levels of several genes associated with survival and migration. Targeting two differentially expressed molecules, NKG2A and Lag-3, reveals differential regulation of 1° and 2° effector functions during pathogen challenge.
PDF
