Systemic Adaptive Immune Responses Research Articles

Very Early Involvement of Innate Immunity in Peripheral Nerve Degeneration in SOD1-G93A Mice.

Recent preclinical and clinical evidence suggest that immune system has a role in the progression and prognosis of Amyotrophic Lateral Sclerosis (ALS), but the identification of a clear mechanism and immune players remains to be elucidated. Here, we have investigated, in 30 and 60 days (presymptomatic) and 120 days (symptomatic) old SOD1-G93A mice, systemic, peripheral, and central innate and adaptive immune and inflammatory response, correlating it with the progression of the neurodegeneration in neuromuscular junction, sciatic nerves, and spinal cord. Surprisingly, we found a very initial (45–60 days) presence of IgG in sciatic nerves together with a gradual enhancement of A20/TNFAIP3 (protein controlling NF-κB signalling) and a concomitantly significant increase and activation of circulating mast cells (MCs) as well as MCs and macrophages in sciatic nerve and an enhancement of IL-6 and IL-10. This immunological frame coincided with a myelin aggregation. The 30–60 days old SOD1-G93A mice didn’t show real elements of neuroinflammation and neurodegeneration in spinal cord. In 120 days old mice macrophages and monocytes are widely diffused in sciatic nerves, peripheral neurodegeneration reaches the tip, high circulating levels of TNFα and IL-2 were found and spinal cord exhibits clear signs of neural damage and infiltrating immune cells. Our results underpin a clear immunological disorder at the origin of ALS axonopathy, in which MCs are involved in the initiation and sustaining of inflammatory events. These data cannot be considered a mere epiphenomenon of motor neuron degeneration and reveal new potential selective immune targets in ALS therapy.

The Immune Phenotype of Isolated Lymphoid Structures in Non-Tumorous Colon Mucosa Encrypts the Information on Pathobiology of Metastatic Colorectal Cancer.

Simple SummaryToday, the presence of well-organized functional structures of immune cells at tumor sites, known as ectopic lymphoid structures, and their strong association with patient survival have been reported in more than ten different cancer types. We aimed to investigate whether there is a link between the patient-specific characteristics of pre-formed isolated lymphoid structures in non-tumorous colon tissue and the disease pathobiology for patients with metastatic colorectal cancer. The study employed a powerful approach of quantitative tissue image cytometry to compare lymphoid structures of different anatomical locations within the same patients. We showed that the properties of isolated lymphoid structures in non-tumorous colon tissue predefine the immune phenotype of ectopic lymphoid structures at primary and metastatic sites. We discovered that B-cell-enriched and highly proliferative lymphoid structures are prognostic towards an improved clinical outcome. The knowledge gained from this study expands our understanding of tumor-immune interactions and draws particular attention to the anti-tumor immune response guided by isolated lymphoid structures outside of tumor tissue.The gut-associated lymphoid tissue represents an integral part of the immune system. Among the powerful players of the mucosa-associated lymphoid tissue are isolated lymphoid structures (ILSs), which as information centers, drive the local (and systemic) adaptive immune responses. Germinal center reactions, taking place within ILSs, involve the coordinated action of various immune cell types with a central role given to B cells. In the current study, we aimed at dissecting the impact of ILSs within non-tumorous colon tissue (NT) on the pathobiology of colorectal cancer (CRC) with metastasis in the liver (CRCLM). In particular, we focused on the immune phenotypes of ILSs and ectopic lymphoid structures (ELSs), built up at matching primary and metastatic tumor sites. We implemented an integrative analysis strategy on the basis of tissue image cytometry and clonality assessment to explore the immune phenotype of ILS/ELS at three tissue entities: NT, CRC, and CRCLM (69 specimens in total). Applying a panel of lineage markers used for immunostaining, we characterized and compared the anatomical features, the cellular composition, the activation, and proliferation status of ILSs and ELSs, and assessed the clinical relevance of staining-derived data sets. Our major discovery was that ILS characteristics at the NT site predefine the immune phenotype of ELSs at CRC and CRCLM. Thereby, B-cell-enriched (CD20) and highly proliferative (Ki67) ILSs and ELSs were found to be associated with improved clinical outcome in terms of survival and enabled patient stratification into risk groups. Moreover, the data revealed a linkage between B-cell clonality at the NT site and the metastatic characteristics of the tumor in the distant liver tissue. Consolidation of immunostaining-based findings with the results of compendium-wide transcriptomic analysis furthermore proposed CD27 as a novel marker of T follicular helper cells within lymphoid structures. Overall, the study nominates the ILS immune phenotype as a novel prognostic marker for patients with metastatic CRC.

Anticipatory plastic response of the cellular immune system in the face of future injury: chronic high perceived predation risk induces lymphocytosis in a cichlid fish

Vertebrate cellular immunity displays substantial variation among taxa and environments. Hematological parameters such as white blood-cell counts have emerged as a valuable tool to understand this variation by assessing the immunological status of individuals. These tools have long revealed that vertebrate cellular immune systems are highly plastic and respond to injury and infection. However, cellular immune systems may also be able to anticipate a high risk of injury from environmental cues (e.g., predation-related cues) and respond plastically ahead of time. We studied white blood-cell (leukocyte) profiles in African cichlids Pelvicachromis taeniatus that were raised for 4 years under different levels of perceived predation risk. In a split-clutch design, we raised fish from hatching onwards under chronic exposure to either conspecific alarm cues (communicating high predation risk) or a distilled water control treatment. Differential blood analysis revealed that alarm cue-exposed fish had twice as many lymphocytes in peripheral blood as did controls, a condition called lymphocytosis. The presence of a higher number of lymphocytes makes the cellular immune response more potent, which accelerates the removal of invading foreign antigens from the bloodstream, and, therefore, may be putatively beneficial in the face of injury. This observed lymphocytosis after long-term exposure to conspecific alarm cues constitutes first evidence for an anticipatory and adaptive plastic response of the cellular immune system to future immunological challenges.

EP01 Post COVID-19 reactive arthritis

Case report - IntroductionWe present what we believe to be the first reported case of post COVID-19 reactive arthritis, in a previously medically well 16-year-old with no past or family history of inflammatory arthritis.Case report - Case descriptionOur patient was a previously medically fit 16-year-old of Caucasian origin who tested positive for COVID-19 in late March 2020. She developed with a 4-day illness with fever, cough, and myalgia from which she made a full and uncomplicated recovery.Ten days later she developed a new erythematous itchy rash on her legs, trunk, and face and a progressive polyarthralgia affecting her MCPs, wrists, shoulders, hips, and knees. The rash typically lasted for 2 days at one site and was non-scarring. This was associated with a low-grade fever. There were no associated mouth ulcers, photosensitivity, alopecia, Raynaud’s, GI disturbance or respiratory symptoms. She had no relevant family history of autoimmunity, psoriasis or inflammatory bowel disease or travel history and had been prescribed no new medications.On examination, she had an erythematous rash on the face in a non malar distribution. She had multiple tender joints without definite synovitis. Cardiovascular, respiratory, gastroenterology and neurological examinations were unremarkable.Investigations revealed a normal full blood count and CRP<1 with normal liver and renal function tests. Her urinalysis was unremarkable. Immunology was negative for ANA, ANCA and rheumatoid factor. Immunoglobulins were normal. Two weeks later her symptoms were fully resolved.Case report - DiscussionCoronaviruses are single-stranded RNA viruses with nearly 30 strains recognised to infect humans. They induce both an innate and adaptive immune system response. It is hypothesised that a dysregulated innate system response, leading to a prolonged adaptive response triggers damaging inflammation and a potential cytokine storm. This is associated with poor outcome during primary viral infection. Variations in this immune response, with different underlying HLA genotypes could lead to other post infectious immune mediated phenomena, such as Paediatric Multisystem Inflammatory Syndrome - Temporally associated with COVID-19.There is a European registry collating data about patients with known rheumatic diseases who are admitted with COVID-19. There is emerging data regarding Paediatric Inflammatory Multisystem Syndrome - Temporally associated with SARS-CoV-2 (PIMS-TS). There is a growing suggestion that a subgroup of patients is developing a COVID-19 associated post viral fatigue syndrome. We suggest that a registry to collect information on de novo autoimmune diseases presenting post COVID-19 is also commenced.Case report - Key learning pointsCOVID-19 infection is associated with a wide variety of sequalae, including rheumatological ones.Classic post viral Reactive arthritis has been seen. A registry to collect information on de novo autoimmune presentations would be highly informative.

Systemic innate and adaptive immune responses to SARS-CoV-2 as it relates to other coronaviruses

ABSTRACT The deadly pandemic caused by the novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) represents one of the greatest threats humanity has faced in the last century. Infection with this easily transmissible virus can run the gamut from asymptomatic to fatal, and the disease caused by SARS-CoV-2 has been termed Coronavirus Disease 2019 (COVID-19). What little research that has already been conducted implicates pathological responses by the immune system as the leading culprit responsible for much of the morbidity and mortality caused by COVID-19. In this review we will summarize what is currently known about the systemic immune response to SARS-CoV-2 and potential immunotherapeutic approaches.

Immune system and types of Immune responses

Immunity is an evolutionarily conserved defense strategy, inherent in both plants and animals, for disease tolerance. It confers the host protection against viral, bacterial, protozoan, and fungal infections. Immune system cells emanate from the bone marrow and subsequently move to the peripheral tissues to defend them. They travel through the bloodstream and the lymphatic system, which is a specialized system of channels. They do so after maturation in the bone marrow These pluripotent hematopoietic stem cells give birth to all types of blood cells, earning them the name pluripotent hematopoietic stem cells. The monocyte, neutrophil, and natural killer (NK) compartments represent the initial line of defense for innate immunological responses among immune cells Adaptive immune system or (behavioral immune response); The adaptive immune system, also known as the acquired immune system, is a part of the immune system that comprises of specialized, systemic cells and processes that kill infections by inhibiting their proliferation. Innate and adaptive immune systems are separated into two categories, each with its own role. Innate immune system or cell-mediated immune response. Adaptive immune system or behavioral immune response. Innate immune system or (cell-mediated immune response); Anti-infection systems in the body's immune response can be engaged swiftly if a pathogen attacks.

Toll-like receptor-2 mediates systemic inflammation in gentamicin-induced rat nephrotoxicity.

Gentamicin is an aminoglycoside antibiotic commonly administrated to patients with Gram-negative infections. Gentamicin induced nephrotoxicity by functional and structural impairment. Toll-like receptors (TLRs) as key mediators in the innate and adaptive immune system response involved in gentamicin-induced nephrotoxicity. The present study aimed to investigate the gene expression of TLR2 and pro-inflammatory cytokines in the renal tissues and buffy coat of the whole blood in gentamicin-treated rats. Twenty adult male Sprague Dawley rats weighing 180-200 were randomly divided into gentamicin (100mg/kg, i.p) and control groups (n=10). After 10days, the serum creatinine (Cr) levels and blood urea nitrogen (BUN) were measured. The mRNA levels of TLR2, tumour necrosis factor (TNF)-α, interleukin (IL)-1β, and monocyte chemoattractant peptide (MCP)-1 were investigated in the renal tissue and buffy coat by qRT-PCR. Kidney histological analysis performed by hematoxylin-eosin (H&E) staining. Functional disturbance is characterized by a significant increase in the serum levels of Cr and BUN in the gentamicin group. Renal tissue slides of the gentamicin group indicated severe glomerular and tubular damage including lobulation of the glomerular tuft, Bowman's space enlargement, acute tubular necrosis, and proximal tubular destruction. The mRNA levels of IL-1β, TNF-α, MCP-1, and TLR2 increased in the buffy coat, but all of them except TLR2 decreased in the renal tissues in the gentamicin group compared with controls. Gentamicin administration induced relative systemic inflammation, which may be related to an increase in the mRNA levels of TLR2 results in gene expression of pro-inflammatory chemokines and cytokines including IL-1β, TNF-α, and MCP-1 in immune cells.

Diverse Virus and Host-Dependent Mechanisms Influence the Systemic and Intrahepatic Immune Responses in the Woodchuck Model of Hepatitis B.

Woodchuck infected with woodchuck hepatitis virus (WHV) represents the pathogenically nearest model of hepatitis B and associated hepatocellular carcinoma (HCC). This naturally occurring animal model also is highly valuable for development and preclinical evaluation of new anti-HBV agents and immunotherapies against chronic hepatitis (CH) B and HCC. Studies in this system uncovered a number of molecular and immunological processes which contribute or likely contribute to the immunopathogenesis of liver disease and modulation of the systemic and intrahepatic innate and adaptive immune responses during hepadnaviral infection. Among them, inhibition of presentation of the class I major histocompatibility complex on chronically infected hepatocytes and a role of WHV envelope proteins in this process, as well as augmented hepatocyte cytotoxicity mediated by constitutively expressed components of CD95 (Fas) ligand- and perforin-dependent pathways, capable of eliminating cells brought to contact with hepatocyte surface, including activated T lymphocytes, were uncovered. Other findings pointed to a role of autoimmune response against hepatocyte asialoglycoprotein receptor in augmenting severity of liver damage in hepadnaviral CH. It was also documented that WHV in the first few hours activates intrahepatic innate immunity that transiently decreases hepatic virus load. However, this activation is not translated in a timely manner to induction of virus-specific T cell response which appears to be hindered by defective activation of antigen presenting cells and presentation of viral epitopes to T cells. The early WHV infection also induces generalized polyclonal activation of T cells that precedes emergence of virus-specific T lymphocyte reactivity. The combination of these mechanisms hinder recognition of virus allowing its dissemination in the initial, asymptomatic stages of infection before adaptive cellular response became apparent. This review will highlight a range of diverse mechanisms uncovered in the woodchuck model which affect effectiveness of the anti-viral systemic and intrahepatic immune responses, and modify liver disease outcomes. Further exploration of these and other mechanisms, either already discovered or yet unknown, and their interactions should bring more comprehensive understanding of HBV pathogenesis and help to identify novel targets for therapeutic and preventive interventions. The woodchuck model is uniquely positioned to further contribute to these advances.

Increased cardiovascular mortality in African Americans with COVID-19

Increased cardiovascular mortality in African Americans with COVID-19

Immunorthodontics: in vivo gene expression of orthodontic tooth movement

Orthodontic tooth movement (OTM) is a “sterile” inflammatory process. The present study aimed to reveal the underlying biological mechanisms, by studying the force associated-gene expression changes, in a time-dependent manner. Ni-Ti springs were set to move the upper 1st-molar in C57BL/6 mice. OTM was measured by μCT. Total-RNA was extracted from tissue blocks at 1,3,7 and 14-days post force application, and from two control groups: naïve and inactivated spring. Gene-expression profiles were generated by next-generation-RNA-sequencing. Gene Set Enrichment Analysis, K-means algorithm and Ingenuity pathway analysis were used for data interpretation. Genes of interest were validated with qRT-PCR. A total of 3075 differentially expressed genes (DEGs) were identified, with the greatest number at day 3. Two distinct clusters patterns were recognized: those in which DEGs peaked in the first days and declined thereafter (tissue degradation, phagocytosis, leukocyte extravasation, innate and adaptive immune system responses), and those in which DEGs were initially down-regulated and increased at day 14 (cell proliferation and migration, cytoskeletal rearrangement, tissue homeostasis, angiogenesis). The uncovering of novel innate and adaptive immune processes in OTM led us to propose a new term “Immunorthodontics”. This genomic data can serve as a platform for OTM modulation future approaches.

Abstract A08: Adenovirus coding for TNF-α and IL-2 proteins mediates abscopal effect in mice receiving anti-PD1 immunotherapy

Abstract Background: Treatment of multiple tumors and metastasis remains a challenge for current therapeutic approaches in cancer treatment. Some responses in noninjected metastases were described in the middle of the last century after using local radiotherapy in breast cancer patients. This phenomenon was named abscopal effect. Nowadays, this effect is well known to be elicited by systemic adaptive immune responses against tumor cells. Of note, it has not been fully reproducible in the clinic mainly due to the suppressive microenvironment surrounding cancer cells. The systemic use of immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1, has shown promise in the treatment of many tumors, but a minority of patients respond. Oncolytic virotherapy is a promising strategy that has emerged in the last few decades. It is able to prime the host immune system against tumor epitopes, thus theoretically complementing aPD1 therapy in an appealing manner. The challenge with oncolytic immunotherapy is that not all metastases can usually be injected. Therefore, it is of importance to study if local treatment can induce distant responses. While our previous work has shown synergy between oncolytic adenovirus and aPD1, here we sought to establish if the synergy extends to noninjected tumors. Aim: In the present study we aimed to assess if local adenovirus injection can impact also noninjected tumors in animals receiving aPD1 therapy. Methods: We utilized a murine melanoma model (B16.OVA) in which each mouse has two tumors, where only one tumor receives local virotherapy and the secondary tumor is studied for possible systemic effects following local injection. Results: Improvement in the overall survival was seen in the group using both therapies (aPD-1 plus virus) compared to the single therapies alone. As well, secondary tumor growth was better controlled in that group. Further information, including the final survival curve, tumor growth and immunologic mechanism-of-action data, will be presented. Conclusion: These two cancer immunotherapeutics seem to be a promising dynamic approach that may increase the life expectancy and cure the patients suffering from metastatic cancer when translated to the clinic, besides minimizing considerably the toxicity due to the specificity of such approach, and finally improving patients’ quality of life during the treatment. Citation Format: Dafne C.A. Quixabeira, Víctor Cervera-Carrascón, Riikka Havunen, Mikko Siurala, Akseli Hemminki. Adenovirus coding for TNF-α and IL-2 proteins mediates abscopal effect in mice receiving anti-PD1 immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A08.

RNA Nanotechnology-Mediated Cancer Immunotherapy.

RNA molecules (e.g., siRNA, microRNA, and mRNA) have shown tremendous potential for immunomodulation and cancer immunotherapy. They can activate both innate and adaptive immune system responses by silencing or upregulating immune-relevant genes. In addition, mRNA-based vaccines have recently been actively pursued and tested in cancer patients, as a form of treatment. Meanwhile, various nanomaterials have been developed to enhance RNA delivery to the tumor and immune cells. In this review article, we summarize recent advances in the development of RNA-based therapeutics and their applications in cancer immunotherapy. We also highlight the variety of nanoparticle platforms that have been used for RNA delivery to elicit anti-tumor immune responses. Finally, we provide our perspectives of potential challenges and opportunities of RNA-based nanotherapeutics in clinical translation towards cancer immunotherapy.

Enhancer jungles establish robust tissue-specific regulatory control in the human genome

An increasing number of studies suggest that functionally redundant enhancers safeguard development via buffering gene expression against environmental and genetic perturbations. Here, we identified over-represented clusters of enhancers (enhancer jungles or EJs) in human B lymphoblastoid cells. We found that EJs tend to associate with genes involved in the activation of the immune system response. Although spanning multiple genes, the enhancers within an EJ tend to collaborate with each other on regulating a single gene. The employment of homotypic transcription factor binding sites (TFBSs) in EJ enhancers and heterotypic TFBSs between constituent enhancers within an EJ may safeguard a robust transcriptional output of the target gene. EJ enhancers evolve under a weaker selective pressure compared to regular enhancers (REs), and approximately 35% of EJs do not have orthologues in the mouse genome. In GM12878, these human-specific EJs appear to regulate genes associated with the adaptive immune system response, while the conserved EJs are associated with innate immunity. Recently acquired human EJs are associated with the higher level of target gene expression compared with conserved EJs, thus facilitating the environmental adaptation of the organism during evolution. In short, the existence of EJs is a common regulatory architecture conferring a robust regulatory control for key lineage genes.

The Influence of Adjuvant Radiotherapy and Single Nucleotide Polymorphisms on Circulating Immune Response Cell Numbers and Phenotypes of Patients With Breast Cancer.

Adjuvant radiotherapy (RT) damages multiple layers of skin, muscle, blood vessels and blood cells that are included within the RT area. Indirect, bystander systemic effects could also develop in cells not directly hit by radiation. Ninety-three female patients recovering from breast cancer surgery and 82 female healthy blood donors were analyzed. For identification of systemic adaptive and innate immune response, rapid and low-cost blood-based biomarkers were assayed. Post-operated breast cancer patients had a decreased number of circulating adaptive immune response cells but increased number of circulating immunosuppressive myeloid subpopulations. RT decreased the number of T-cells and platelets without influencing the number of immunosuppressive myeloid subpopulations. Alterations in the number and phenotypes of T-cell subpopulations were associated with SNPs. The combination of RT and immunotherapy might provide optimal treatment for cancer patients.

1698-P: Integrative Genomics Analysis Reveals Tissue-Specific Pathways and Gene Networks for Type 1 Diabetes

Type 1 diabetes (T1D) is a complex disease involving genetic predisposition that interacts with environmental triggers, leading to the loss of insulin producing beta cells. However, the molecular cascades underlying T1D are poorly understood. We hypothesize that genetic risk factors of T1D perturb tissue-specific biological pathways and gene networks, ultimately leading to the pathogenic end point in beta cells. We sought to identify the gene networks and key regulators for T1D by conducting a comprehensive, data-driven multi-omics analysis that integrates human genome-wide association studies (GWAS) of T1D, tissue-specific genetic regulation of gene expression in the form of expression quantitative trait loci (eQTLs), and tissue-specific gene network models using a computational pipeline Mergeomics. Our analysis revealed immune pathways such as adaptive immune system, cytokines and inflammatory response, primary immunodeficiency and immunoregulatory interactions between a Lymphoid and non-Lymphoid cell, across various tissues as well as tissue-specific signals such as regulation of complement cascade, class B/2 (Secretin family receptors) and neuroactive ligand-receptor interaction. Our integrative genomics approach offers comprehensive insights into the tissue-specific molecular networks and regulators underlying T1D. Disclosure M. Blencowe: None. Z. Saleem: None. X. Yang: None. Funding National Institutes of Health (R01DK104363)

MicroRNA modulated networks of adaptive and innate immune response in pancreatic ductal adenocarcinoma.

Despite progress in treatment strategies, only ~24% of pancreatic ductal adenocarcinoma (PDAC) patients survive >1 year. Our goal was to elucidate deregulated pathways modulated by microRNAs (miRNAs) in PDAC and Vater ampulla (AMP) cancers. Global miRNA expression was identified in 19 PDAC, 6 AMP and 25 paired, histologically normal pancreatic tissues using the GeneChip 4.0 miRNA arrays. Computational approaches were used for miRNA target prediction/identification of miRNA-regulated pathways. Target gene expression was validated in 178 pancreatic cancer and 4 pancreatic normal tissues from The Cancer Genome Atlas (TCGA). 20 miRNAs were significantly deregulated (FC≥2 and p<0.05) (15 down- and 5 up-regulated) in PDAC. miR-216 family (miR-216a-3p, miR-216a-5p, miR-216b-3p and miR-216b-5p) was consistently down-regulated in PDAC. miRNA-modulated pathways are associated with innate and adaptive immune system responses in PDAC. AMP cancers showed 8 down- and 1 up-regulated miRNAs (FDR p<0.05). Most enriched pathways (p<0.01) were RAS and Nerve Growth Factor signaling. PDAC and AMP display different global miRNA expression profiles and miRNA regulated networks/tumorigenesis pathways. The immune response was enriched in PDAC, suggesting the existence of immune checkpoint pathways more relevant to PDAC than AMP.

Combining activatable nanodelivery with immunotherapy in a murine breast cancer model

A successful chemotherapy-immunotherapy solid-tumor protocol should accomplish the following goals: debulk large tumors, release tumor antigen for cross-presentation and cross-priming, release cancer-suppressive cytokines and enhance anti-tumor immune cell populations. Thermally-activated drug delivery particles have the potential to synergize with immunotherapeutics to accomplish these goals; activation can release chemotherapy within bulky solid tumors and can enhance response when combined with immunotherapy. We set out to determine whether a single protocol, combining locally-activated chemotherapy and agonist immunotherapy, could accomplish these goals and yield a potentially translational therapy. For effective delivery of free doxorubicin to tumors with minimal toxicity, we stabilized doxorubicin with copper in temperature-sensitive liposomes that rapidly release free drug in the vasculature of cancer lesions upon exposure to ultrasound-mediated hyperthermia. We found that in vitro exposure of tumor cells to hyperthermia and doxorubicin resulted in immunogenic cell death and the local release of type I interferons across murine cancer cell lines. Following intravenous injection, local activation of the liposomes within a single tumor released doxorubicin and enhanced cross-presentation of a model antigen at distant tumor sites. While a variety of protocols achieved a complete response in >50% of treated mice, the complete response rate was greatest (90%) when 1 week of immunotherapy priming preceded a single activatable chemotherapeutic administration. While repeated chemotherapeutic delivery reduced local viable tumor, the complete response rate and a subset of tumor immune cells were also reduced. Taken together, the results suggest that activatable chemotherapy can enhance adjuvant immunotherapy; however, in a murine model the systemic adaptive immune response was greatest with a single administration of chemotherapy.

SABR Produces Systemic Adaptive Immune Responses in Castration-Sensitive Oligometastatic Prostate Cancer Patients

SABR Produces Systemic Adaptive Immune Responses in Castration-Sensitive Oligometastatic Prostate Cancer Patients

Estriol Reduces Pulmonary Immune Cell Recruitment and Inflammation to Protect Female Mice From Severe Influenza.

Estriol (E3) is an endogenous estrogen in females with broad biological activity within diverse tissue types. In the context of certain T-cell-mediated autoimmune inflammatory diseases, E3 can ameliorate disease severity through immunomodulatory mechanisms that decrease tissue inflammation. Severe disease caused by influenza A virus (IAV) infection is also characterized by aberrant inflammation and immunopathology. How E3 might affect the pathogenesis of IAV infection, however, has not been explored. Gonadally intact female C57BL/6 mice that were treated with exogenous E3 during infection with mouse-adapted 2009 H1N1 had reduced total pulmonary inflammation and improved disease outcomes compared with females that received no hormone. Furthermore, compared with no hormone treatment, E3 treatment reduced the induction of genes associated with proinflammatory cytokine and chemokine responses in the lungs, which preceded clinical disease, reductions in innate immune cell recruitment, altered pulmonary T-cell skewing, and reduced antibody titers during IAV infection. Although E3 treatment was associated with reduced local and systemic anti-influenza adaptive immune responses, there was no effect of E3 on viral replication or clearance. Together, these data suggest that exogenous E3 confers protection during IAV infection through immunomodulatory mechanisms and that E3 may have broad therapeutic potential in the context of both infectious and noninfectious inflammatory diseases.

Oncolytic Reovirus and Immune Checkpoint Inhibition as a Novel Immunotherapeutic Strategy for Breast Cancer.

As the current efficacy of oncolytic viruses (OVs) as monotherapy is limited, exploration of OVs as part of a broader immunotherapeutic treatment strategy for cancer is necessary. Here, we investigated the ability for immune checkpoint blockade to enhance the efficacy of oncolytic reovirus (RV) for the treatment of breast cancer (BrCa). In vitro, oncolysis and cytokine production were assessed in human and murine BrCa cell lines following RV exposure. Furthermore, RV-induced upregulation of tumor cell PD-L1 was evaluated. In vivo, the immunocompetent, syngeneic EMT6 murine model of BrCa was employed to determine therapeutic and tumor-specific immune responses following treatment with RV, anti-PD-1 antibodies or in combination. RV-mediated oncolysis and cytokine production were observed following BrCa cell infection and RV upregulated tumor cell expression of PD-L1. In vivo, RV monotherapy significantly reduced disease burden and enhanced survival in treated mice, and was further enhanced by PD-1 blockade. RV therapy increased the number of intratumoral regulatory T cells, which was reversed by the addition of PD-1 blockade. Finally, dual treatment led to the generation of a systemic adaptive anti-tumor immune response evidenced by an increase in tumor-specific IFN-γ producing CD8+ T cells, and immunity from tumor re-challenge. The combination of PD-1 blockade and RV appears to be an efficacious immunotherapeutic strategy for the treatment of BrCa, and warrants further investigation in early-phase clinical trials.