In Vivo Labeling Resolves Distinct Temporal, Spatial, and Functional Properties of Tumor Macrophages and Identifies Subset-Specific Effects of PD-L1 Blockade.

Tumor-associated macrophages (TAM) are a universal feature of cancers but variably influence outcomes and treatment responses. In this study, we used a photoconvertible mouse to distinguish newly entering, monocyte-derived TAMs (mdTAM) that were enriched at the tumor core from resident-like TAMs that localized with fibroblasts at the tumor-normal interface. The mdTAM pool was highly dynamic and continually replenished by circulating monocytes.

Emerging in vivo tools for ILC2 research.

ILC2 are critical regulators of inflammation and tissue homeostasis in diverse anatomical sites. ILC2-targeted mouse models have underpinned this emerging field of research. In this issue of JEM, (Kabil et al.

IL-33 and ILC2 in pancreatic cancer: good, bad or a bit of both?

Tertiary lymphoid structures (TLS) are associated with anticancer immunity, but the mechanisms underpinning their formation remain poorly understood. Amisaki et al. have recently shown that IL-33 mediates ILC2 gut-tumoral migration and promotes TLS formation in pancreatic ductal adenocarcinoma (PDAC) by inducing group 2 innate lymphoid cell (ILC2) Ltb expression.

Cross-talk between ILC2 and Gata3 T locally constrains adaptive type 2 immunity.

Regulatory T cells (T) control adaptive immunity and restrain type 2 inflammation in allergic disease. Interleukin-33 promotes the expansion of tissue-resident T and group 2 innate lymphoid cells (ILC2s); however, how T locally coordinate their function within the inflammatory niche is not understood. Here, we show that ILC2s are critical orchestrators of T function.

Intratumoral antigen signaling traps CD8 T cells to confine exhaustion to the tumor site.

Immunotherapy advances have been hindered by difficulties in tracking the behaviors of lymphocytes after antigen signaling. Here, we assessed the behavior of T cells active within tumors through the development of the antigen receptor signaling reporter (AgRSR) mouse, fate-mapping lymphocytes responding to antigens at specific times and locations. Contrary to reports describing the ready egress of T cells out of the tumor, we find that intratumoral antigen signaling traps CD8 T cells in the tumor.

BACH2 restricts NK cell maturation and function, limiting immunity to cancer metastasis.

Natural killer (NK) cells are critical to immune surveillance against infections and cancer. Their role in immune surveillance requires that NK cells are present within tissues in a quiescent state. Mechanisms by which NK cells remain quiescent in tissues are incompletely elucidated.

Context-dependent effects of IL-2 rewire immunity into distinct cellular circuits.

Interleukin 2 (IL-2) is a key homeostatic cytokine, with therapeutic applications in both immunogenic and tolerogenic immune modulation. Clinical use has been hampered by pleiotropic functionality and widespread receptor expression, with unexpected adverse events. Here, we developed a novel mouse strain to divert IL-2 production, allowing identification of contextual outcomes.

Senescence-induced endothelial phenotypes underpin immune-mediated senescence surveillance.

Senescence is a stress-responsive tumor suppressor mechanism associated with expression of the senescence-associated secretory phenotype (SASP). Through the SASP, senescent cells trigger their own immune-mediated elimination, which if evaded leads to tumorigenesis. Senescent parenchymal cells are separated from circulating immunocytes by the endothelium, which is targeted by microenvironmental signaling.

Early Neutrophilia Marked by Aerobic Glycolysis Sustains Host Metabolism and Delays Cancer Cachexia.

An elevated neutrophil-lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, using murine model systems of colorectal and pancreatic cancer we show that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, similar to cancer cells.

Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors.

It is unclear how genetic aberrations impact the state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) has been shown to arise from luminal progenitors yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge.

ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung.

Metastasis constitutes the primary cause of cancer-related deaths, with the lung being a commonly affected organ. We found that activation of lung-resident group 2 innate lymphoid cells (ILC2s) orchestrated suppression of natural killer (NK) cell-mediated innate antitumor immunity, leading to increased lung metastases and mortality. Using multiple models of lung metastasis, we show that interleukin (IL)-33-dependent ILC2 activation in the lung is involved centrally in promoting tumor burden.

Context Dependent Role of Type 2 Innate Lymphoid Cells in Allergic Skin Inflammation.

The discovery of innate lymphoid cells (ILC) has profoundly influenced the understanding of innate and adaptive immune crosstalk in health and disease. ILC and T cells share developmental and functional characteristics such as the lineage-specifying transcription factors and effector cytokines, but importantly ILC do not display rearranged antigen-specific receptors. Similar to T cells ILC are subdivided into 3 different helper-like subtypes, namely ILC1-3, and a killer-like subtype comprising natural killer (NK) cells.

Regulation of regulatory T cells in cancer.

The inflammatory response to transformed cells forms the cornerstone of natural or therapeutically induced protective immunity to cancer. Regulatory T (Treg) cells are known for their critical role in suppressing inflammation, and therefore can antagonize effective anti-cancer immune responses. As such, Treg cells can play detrimental roles in tumour progression and in the response to both conventional and immune-based cancer therapies.

Tissue-Restricted Adaptive Type 2 Immunity Is Orchestrated by Expression of the Costimulatory Molecule OX40L on Group 2 Innate Lymphoid Cells.

The local regulation of type 2 immunity relies on dialog between the epithelium and the innate and adaptive immune cells. Here we found that alarmin-induced expression of the co-stimulatory molecule OX40L on group 2 innate lymphoid cells (ILC2s) provided tissue-restricted T cell co-stimulation that was indispensable for Th2 and regulatory T (Treg) cell responses in the lung and adipose tissue. Interleukin (IL)-33 administration resulted in organ-specific surface expression of OX40L on ILC2s and the concomitant expansion of Th2 and Treg cells, which was abolished upon deletion of OX40L on ILC2s (Il7raTnfsf4 mice).

Lack of Type 2 Innate Lymphoid Cells Promotes a Type I-Driven Enhanced Immune Response in Contact Hypersensitivity.

Allergic contact dermatitis and its animal model, contact hypersensitivity, are T-cell-mediated inflammatory skin diseases that require activation of the innate immune system. Here we investigate the role of innate lymphoid cells (ILCs) during the elicitation phase of 2,4,6-trinitrochlorobenzene-induced contact hypersensitivity using Eomes x Rorc(γt)-Cre x Rosa26R reporter mice. Ear swelling responses, cutaneous ILC numbers, and cytokine production were determined at different time points.

Group 2 innate lymphocytes at the interface between innate and adaptive immunity.

Group 2 innate lymphoid cells (ILC2) are innate immune cells that respond rapidly to their environment through soluble inflammatory mediators and cell-to-cell interactions. As tissue-resident sentinels, ILC2 help orchestrate localized type 2 immune responses. These ILC2-driven type 2 responses are now recognized in diverse immune processes, different anatomical locations, and homeostatic or pathological settings.

Common-Lymphoid-Progenitor-Independent Pathways of Innate and T Lymphocyte Development.

All lymphocytes are thought to develop from common lymphoid progenitors (CLPs). However, lymphoid-primed multipotent progenitors (LMPPs) are more efficient than CLPs in differentiating into T cells and group 2 innate lymphoid cells (ILC2s). Here, we have divided LMPPs into CD127(-) (LMPP-s) and CD127(+) (LMPP+s) subsets and compared them with Ly6D(-) and Ly6D(+) CLPs.

Group 2 innate lymphoid cells license dendritic cells to potentiate memory TH2 cell responses.

Rapid activation of memory CD4(+) T helper 2 (TH2) cells during allergic inflammation requires their recruitment into the affected tissue. Here we demonstrate that group 2 innate lymphoid (ILC2) cells have a crucial role in memory TH2 cell responses, with targeted depletion of ILC2 cells profoundly impairing TH2 cell localization to the lungs and skin of sensitized mice after allergen re-challenge. ILC2-derived interleukin 13 (IL-13) is critical for eliciting production of the TH2 cell-attracting chemokine CCL17 by IRF4(+)CD11b(+)CD103(-) dendritic cells (DCs).

Group 2 innate lymphoid cells in disease.

Group 2 innate lymphoid cells (ILC2) are now recognized as an important innate source of type-2 effector cytokines. Although initially associated with mucosal tissues, it is clear that ILC2 are present in diverse anatomical locations. The function of ILC2 at these sites is equally varied, and although ILC2 represent a relatively minor population, they are fundamentally important regulators of innate and adaptive immune processes.

Isolation and characterization of mouse innate lymphoid cells.

Innate lymphoid cells (ILCs) are rare populations of cytokine-producing lymphocytes and are divided into three groups, namely ILC1, ILC2, and ILC3, based on the cytokines that they produce. They comprise less than 1% of lymphocytes in mucosal tissues and express no unique cell surface markers. Therefore, they can only be identified by combinations of multiple cell surface markers and further characterized by cytokine production in vitro.

Group 2 innate lymphoid cells facilitate sensitization to local, but not systemic, TH2-inducing allergen exposures.

Background: Allergic inflammation involves the sensitization of naive CD4(+) T cells to allergens, resulting in a TH2-skewed inflammatory response. Although antigen presentation by dendritic cells to T cells in the lymph node is crucial for TH2 cell development, the innate signals that initiate adaptive type 2 inflammation and the role of group 2 innate lymphoid cells (ILC2s) are poorly understood.

Objective: We sought to investigate the influence of ILC2s and the route of priming on the development of an adaptive type 2 immune response to lung allergens.

Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation.

Naive CD4(+) T cell differentiation into distinct subsets of T helper (Th) cells is a pivotal process in the initiation of the adaptive immune response. Allergens predominantly stimulate Th2 cells, causing allergic inflammation. However, why allergens induce Th2 cell differentiation is not well understood.

New kids on the block: group 2 innate lymphoid cells and type 2 inflammation in the lung.

Inflammatory diseases of the lung are a major cause of morbidity and mortality. Allergic lung inflammation often stems from the overproduction of type 2 cytokines. The resulting type 2 inflammation is frequently caused by an inappropriate immune response to relatively harmless allergens and often associates with asthma.

Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation.

Natural helper (NH) cells are innate lymphoid cells (ILCs) that produce T helper-2 (Th2)-cell-type cytokines in the lung- and gut-associated lymphoid tissues. Currently, the lineage relationship between NH cells in different tissues and between NH cells and interleukin-22 (IL-22)-producing retinoic-acid-receptor-related orphan receptor (ROR)γt-positive ILCs is unclear. Here, we report that NH cells express RORα, but not RORγt.