Role of the microbiota in response to and recovery from cancer therapy.

Our understanding of how the microbiota affects the balance between response to and failure of cancer treatment by modulating the tumour microenvironment and systemic immune system has advanced rapidly in recent years. Microbiota-targeting interventions in patients with cancer are an area of intensive investigation. Promisingly, phase I-II clinical trials have shown that interventions such as faecal microbiota transplantation can overcome resistance to immune checkpoint blockade in patients with melanoma, improve therapeutic outcomes in treatment-naive patients and reduce therapy-induced immunotoxicities.

The landscape of T cell antigens for cancer immunotherapy.

The remarkable capacity of immunotherapies to induce durable regression in some patients with metastatic cancer relies heavily on T cell recognition of tumor-presented antigens. As checkpoint-blockade therapy has limited efficacy, tumor antigens have the potential to be exploited for complementary treatments, many of which are already in clinical trials. The surge of interest in this topic has led to the expansion of the tumor antigen landscape with the emergence of new antigen categories.

Neoantigens in cancer immunotherapy: quantity vs. quality.

Traditional immunotherapies provide clinical benefits to only a few patients with solid tumors, highlighting the urgent need for more effective approaches. Traditional immunotherapies rely on the presentation of cancer antigens, with neoantigens being highly important in this context as they are specific to malignant tissue but not healthy tissue. The quantity of neoantigens is often associated with clinical benefit, but it cannot fully explain or predict patient response.

Fecal Microbiota Transplantation as a Cancer Therapeutic.

For decades, cancer research and treatment focused on the cellular level, viewing cancer as a genetic disease of cell transformation. In the era of chemotherapy and radiotherapy, studies from the second half of the 19th century suggesting an association between the microbiota and cancer were almost neglected. The main focus of the field was limited to identification of specific viruses and bacteria that may serve as direct carcinogens leading to the recognition of 7 viruses (i.

Intratumor Heterogeneity and Antitumor Immunity Shape One Another Bidirectionally.

Over the last decade, it has become clear that the genomic landscapes of tumors profoundly impact their immunogenicity and how tumor cells interact with immune cells. Whereas past discoveries mainly focused on the interplay between tumor immunogenicity and tumor mutational burden (TMB), under the assumption that a higher mutation load would give rise to a better patient response to immune checkpoint blockade therapies, we and others have underlined intratumor heterogeneity (ITH) as an important determinant of the magnitude of the antitumor response and the nature of the tumor microenvironment. In this review, we define TMB versus ITH and how the two factors are being inferred from data, examine key findings in the cancer immunogenomics literature deciphering the complex cross-talk between TMB, ITH, and antitumor immunity in human cancers and in vivo models, and discuss the mutual influence of ITH and immunity-how the antitumor response can give rise to tumors with higher ITH, and how higher ITH can put shackles on the antitumor response.

Supporting the Next Generation of Scientists to Lead Cancer Immunology Research.

Recent success in the use of immunotherapy for a broad range of cancers has propelled the field of cancer immunology to the forefront of cancer research. As more and more young investigators join the community of cancer immunologists, the Arthur L. Irving Family Foundation Cancer Immunology Symposium provided a platform to bring this expanding and vibrant community together and support the development of the future leaders in the field.

Polyglutamine-Related Aggregates Can Serve as a Potent Antigen Source for Cross-Presentation by Dendritic Cells.

Protective MHC class I-dependent immune responses require an overlap between repertoires of proteins directly presented on target cells and cross-presented by professional APC, specifically dendritic cells. How stable proteins that rely on defective ribosomal proteins for direct presentation are captured for cell-to-cell transfer remains enigmatic. In this study, we address this issue using a combination of in vitro (C57BL/6-derived mouse cell lines) and in vivo (C57BL/6 mouse strains) approaches involving stable and unstable versions of OVA model Ags displaying defective ribosomal protein-dependent and -independent Ag presentation, respectively.

Bone marrow dendritic cells support the survival of chronic lymphocytic leukemia cells in a CD84 dependent manner.

Chronic lymphocytic leukemia (CLL) is a malignancy of mature B lymphocytes. The microenvironment of the CLL cells is a vital element in the regulation of the survival of these malignant cells. CLL cell longevity is dependent on external signals, originating from cells in their microenvironment including secreted and surface-bound factors.

TIM3 comes of age as an inhibitory receptor.

T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), a member of the TIM family, was originally identified as a receptor expressed on interferon-γ-producing CD4 and CD8 T cells. Initial data indicated that TIM3 functioned as a 'co-inhibitory' or 'checkpoint' receptor, but due to the lack of a definable inhibitory signalling motif, it was also suggested that TIM3 might act as a co-stimulatory receptor. Recent studies have shown that TIM3 is part of a module that contains multiple co-inhibitory receptors (checkpoint receptors), which are co-expressed and co-regulated on dysfunctional or 'exhausted' T cells in chronic viral infections and cancer.

UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma.

Although clonal neo-antigen burden is associated with improved response to immune therapy, the functional basis for this remains unclear. Here we study this question in a novel controlled mouse melanoma model that enables us to explore the effects of intra-tumor heterogeneity (ITH) on tumor aggressiveness and immunity independent of tumor mutational burden. Induction of UVB-derived mutations yields highly aggressive tumors with decreased anti-tumor activity.

Cancer research in the era of immunogenomics.

The most meaningful advancement in cancer treatment in recent years has been the emergence of immunotherapy. Checkpoint inhibitor blockade and adoptive T cell therapy have shown remarkable clinical effects in a wide range of tumour types. Despite these advances, many tumours do not respond to these treatments, which raises the need to further investigate how patients can benefit from immunotherapy.

Microglial MHC class II is dispensable for experimental autoimmune encephalomyelitis and cuprizone-induced demyelination.

Microglia are resident immune cells in the CNS, strategically positioned to clear dead cells and debris, and orchestrate CNS inflammation and immune defense. In steady state, these macrophages lack MHC class II (MHCII) expression, but microglia activation can be associated with MHCII induction. Whether microglial MHCII serves antigen presentation for critical local T-cell restimulation in CNS auto-immune disorders or modulates microglial signaling output remains under debate.

Induced-Pluripotent-Stem-Cell-Derived Primitive Macrophages Provide a Platform for Modeling Tissue-Resident Macrophage Differentiation and Function.

Tissue macrophages arise during embryogenesis from yolk-sac (YS) progenitors that give rise to primitive YS macrophages. Until recently, it has been impossible to isolate or derive sufficient numbers of YS-derived macrophages for further study, but data now suggest that induced pluripotent stem cells (iPSCs) can be driven to undergo a process reminiscent of YS-hematopoiesis in vitro. We asked whether iPSC-derived primitive macrophages (iMacs) can terminally differentiate into specialized macrophages with the help of growth factors and organ-specific cues.

Brown-adipose-tissue macrophages control tissue innervation and homeostatic energy expenditure.

Tissue macrophages provide immunological defense and contribute to the establishment and maintenance of tissue homeostasis. Here we used constitutive and inducible mutagenesis to delete the nuclear transcription regulator Mecp2 in macrophages. Mice that lacked the gene encoding Mecp2, which is associated with Rett syndrome, in macrophages did not show signs of neurodevelopmental disorder but displayed spontaneous obesity, which was linked to impaired function of brown adipose tissue (BAT).

Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis.

Adaptive thermogenesis is the process of heat generation in response to cold stimulation. It is under the control of the sympathetic nervous system, whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through β3-adrenergic receptors to activate brown adipose tissue and by 'browning' white adipose tissue.

Autonomous TNF is critical for in vivo monocyte survival in steady state and inflammation.

Monocytes are circulating mononuclear phagocytes, poised to extravasate to sites of inflammation and differentiate into monocyte-derived macrophages and dendritic cells. Tumor necrosis factor () and its receptors are up-regulated during monopoiesis and expressed by circulating monocytes, as well as effector monocytes infiltrating certain sites of inflammation, such as the spinal cord, during experimental autoimmune encephalomyelitis (EAE). In this study, using competitive in vitro and in vivo assays, we show that monocytes deficient for or receptors are outcompeted by their wild-type counterpart.

Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression.

Microglia, the resident CNS macrophages, have been implicated in the pathogenesis of Rett Syndrome (RTT), an X-linked neurodevelopmental disorder. However, the mechanism by which microglia contribute to the disorder is unclear and recent data suggest that microglia do not play a causative role. Here, we use the retinogeniculate system to determine if and how microglia contribute to pathogenesis in a RTT mouse model, the Mecp2 null mouse (Mecp2(tm1.

Microglia replenished OHSC: A culture system to study in vivo like adult microglia.

Recent data suggest that ramified microglia fulfil various tasks in the brain. However, to investigate this unique cell type cultured primary microglia are only a poor model. We here describe a method to deplete and repopulate organotypic hippocampal slice cultures (OHSC) with ramified microglia isolated from adult mouse brain creating microglia-replenished OHSC (Mrep-OHSC).

Macrophage precursor cells from the left atrial appendage of the heart spontaneously reprogram into a C-kit+/CD45- stem cell-like phenotype.

Background: The developmental origin of the c-kit expressing progenitor cell pool in the adult heart has remained elusive. Recently, it has been discovered that the injured heart is enriched with c-kit(+) cells, which also express the hematopoietic marker CD45.

Methods And Results: In this study, we characterize the phenotype and transcriptome of the c-kit+/CD45+/CD11b+/Flk-1+/Sca-1±(B-type) cell population, originating from the left atrial appendage.

Adaptive Immune Regulation of Mammary Postnatal Organogenesis.

Postnatal organogenesis occurs in an immune competent environment and is tightly controlled by interplay between positive and negative regulators. Innate immune cells have beneficial roles in postnatal tissue remodeling, but roles for the adaptive immune system are currently unexplored. Here we show that adaptive immune responses participate in the normal postnatal development of a non-lymphoid epithelial tissue.

Genetic Cell Ablation Reveals Clusters of Local Self-Renewing Microglia in the Mammalian Central Nervous System.

During early embryogenesis, microglia arise from yolk sac progenitors that populate the developing central nervous system (CNS), but how the tissue-resident macrophages are maintained throughout the organism's lifespan still remains unclear. Here, we describe a system that allows specific, conditional ablation of microglia in adult mice. We found that the microglial compartment was reconstituted within 1 week of depletion.

Methyl-CpG Binding Protein 2 Regulates Microglia and Macrophage Gene Expression in Response to Inflammatory Stimuli.

Mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2, are the predominant cause of Rett syndrome, a disease characterized by both neurological symptoms and systemic abnormalities. Microglial dysfunction is thought to contribute to disease pathogenesis, and here we found microglia become activated and subsequently lost with disease progression in Mecp2-null mice. Mecp2 was found to be expressed in peripheral macrophage and monocyte populations, several of which also became depleted in Mecp2-null mice.

Progressive replacement of embryo-derived cardiac macrophages with age.

Cardiac macrophages (cMΦ) are critical for early postnatal heart regeneration and fibrotic repair in the adult heart, but their origins and cellular dynamics during postnatal development have not been well characterized. Tissue macrophages can be derived from embryonic progenitors or from monocytes during inflammation. We report that within the first weeks after birth, the embryo-derived population of resident CX3CR1(+) cMΦ diversifies into MHCII(+) and MHCII(-) cells.