Same-Slide Spatial Multi-Omics Integration Reveals Tumor Virus-Linked Spatial Reorganization of the Tumor Microenvironment.

The advent of spatial transcriptomics and spatial proteomics have enabled profound insights into tissue organization to provide systems-level understanding of diseases. Both technologies currently remain largely independent, and emerging same slide spatial multi-omics approaches are generally limited in plex, spatial resolution, and analytical approaches. We introduce IN-situ DEtailed Phenotyping To High-resolution transcriptomics (IN-DEPTH), a streamlined and resource-effective approach compatible with various spatial platforms.

Alarm Functions of PD-1+ Brain-Resident Memory T Cells.

Resident memory T cells (TRM cells) have been described in barrier tissues as having a "sensing and alarm" function where, upon sensing cognate Ag, they alarm the surrounding tissue and orchestrate local recruitment and activation of immune cells. In the immunologically unique and tightly restricted CNS, it remains unclear whether and how brain TRM cells, which express the inhibitory receptor programmed cell death protein 1 (PD-1), alarm the surrounding tissue during Ag re-encounter. Using mouse models, we reveal that TRM cells are sufficient to drive the rapid remodeling of the brain immune landscape through activation of microglia, dendritic cells, NK cells, and B cells, expansion of regulatory T cells, and recruitment of macrophages and monocytic dendritic cells.

Emergency myelopoiesis in solid cancers.

Cells of the innate and adaptive immune systems are the progeny of haematopoietic stem and progenitor cells (HSPCs). During steady-state myelopoiesis, HSPC undergo differentiation and proliferation but are called to respond directly and acutely to various signals that lead to emergency myelopoiesis, including bone marrow ablation, infections, and sterile inflammation. There is extensive evidence that many solid tumours have the potential to secrete classical myelopoiesis-promoting growth factors and other products able to mimic emergency haematopoiesis, and to aberrantly re-direct myeloid cell development into immunosuppressive cells with tumour promoting properties.

Alarm functions of PD-1+ brain resident memory T cells.

Resident memory T cells (T ) have been described in barrier tissues as having a 'sensing and alarm' function where, upon sensing cognate antigen, they alarm the surrounding tissue and orchestrate local recruitment and activation of immune cells. In the immunologically unique and tightly restricted CNS, it remains unclear if and how brain T , which express the inhibitory receptor PD-1, alarm the surrounding tissue during antigen re-encounter. Here, we reveal that T are sufficient to drive the rapid remodeling of the brain immune landscape through activation of microglia, DCs, NK cells, and B cells, expansion of Tregs, and recruitment of macrophages and monocytic dendritic cells.

Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.

Obesity is a leading risk factor for progression and metastasis of many cancers, yet can in some cases enhance survival and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-1.

A four-cell pathway orchestrated by Flt3-L-dependent cDCs controls anti-tumor responses.

A study by Régnier et al. shows that Flt3-ligand (FL) levels program two distinct mechanisms of anti-tumor immunity. Low FL levels allow recruitment of T effectors and T cell-mediated responses whereas high FL levels support recruitment of classical dendritic cells (cDC) and natural killer (NK) cells and NK-mediated anti-tumor responses.

Soluble PD-L1 reprograms blood monocytes to prevent cerebral edema and facilitate recovery after ischemic stroke.

Acute cerebral ischemia triggers a profound inflammatory response. While macrophages polarized to an M2-like phenotype clear debris and facilitate tissue repair, aberrant or prolonged macrophage activation is counterproductive to recovery. The inhibitory immune checkpoint Programmed Cell Death Protein 1 (PD-1) is upregulated on macrophage precursors (monocytes) in the blood after acute cerebrovascular injury.

The role of ROS in tumor infiltrating immune cells and cancer immunotherapy.

Reactive oxygen species (ROS) are a group of short-lived highly reactive molecules formed intracellularly from molecular oxygen. ROS can alter biochemical, transcriptional, and epigenetic programs and have an indispensable role in cellular function. In immune cells, ROS are mediators of specialized functions such as phagocytosis, antigen presentation, activation, cytolysis, and differentiation.

Combined thermal ablation and liposomal granulocyte-macrophage colony stimulation factor increases immune cell trafficking in a small animal tumor model.

Purpose: To characterize intratumoral immune cell trafficking in ablated and synchronous tumors following combined radiofrequency ablation (RFA) and systemic liposomal granulocyte-macrophage colony stimulation factor (lip-GM-CSF).

Methods: Phase I, 72 rats with single subcutaneous R3230 adenocarcinoma were randomized to 6 groups: a) sham; b&c) free or liposomal GM-CSF alone; d) RFA alone; or e&f) combined with blank liposomes or lip-GM-CSF. Animals were sacrificed 3 and 7 days post-RFA.

Immune-related adverse effects of checkpoint immunotherapy and implications for the treatment of patients with cancer and autoimmune diseases.

During the past decade, there has been a revolution in cancer therapeutics by the emergence of antibody-based immunotherapies that modulate immune responses against tumors. These therapies have offered treatment options to patients who are no longer responding to classic anti-cancer therapies. By blocking inhibitory signals mediated by surface receptors that are naturally upregulated during activation of antigen-presenting cells (APC) and T cells, predominantly PD-1 and its ligand PD-L1, as well as CTLA-4, such blocking agents have revolutionized cancer treatment.

Driver Mutations Dictate the Immunologic Landscape and Response to Checkpoint Immunotherapy of Glioblastoma.

The composition of the tumor immune microenvironment (TIME) is considered a key determinant of patients' response to immunotherapy. The mechanisms underlying TIME formation and development over time are poorly understood. Glioblastoma (GBM) is a lethal primary brain cancer for which there are no curative treatments.

SHP-2 and PD-1-SHP-2 signaling regulate myeloid cell differentiation and antitumor responses.

The inhibitory receptor PD-1 suppresses T cell activation by recruiting the phosphatase SHP-2. However, mice with a T-cell-specific deletion of SHP-2 do not have improved antitumor immunity. Here we showed that mice with conditional targeting of SHP-2 in myeloid cells, but not in T cells, had diminished tumor growth.

Immune cellular components and signaling pathways in the tumor microenvironment.

During the past decade there has been a revolution in cancer therapeutics by the emergence of antibody-based and cell-based immunotherapies that modulate immune responses against tumors. These new therapies have extended and improved the therapeutic efficacy of chemo-radiotherapy and have offered treatment options to patients who are no longer responding to these classic anti-cancer treatments. Unfortunately, tumor eradication and long-lasting responses are observed in a small fraction of patients, whereas the majority of patients respond only transiently.

The evolving role of tissue-resident memory T cells in infections and cancer.

Resident memory T cells (T) form a distinct type of T memory cells that stably resides in tissues. T form an integral part of the immune sensing network and have the ability to control local immune homeostasis and participate in immune responses mediated by pathogens, cancer, and possibly autoantigens during autoimmunity. T express residence gene signatures, functional properties of both memory and effector cells, and remarkable plasticity.

The complex role of tumor-infiltrating macrophages.

Long recognized as an evolutionarily ancient cell type involved in tissue homeostasis and immune defense against pathogens, macrophages are being re-discovered as regulators of several diseases, including cancer. Tumor-associated macrophages (TAMs) represent the most abundant innate immune population in the tumor microenvironment (TME). Macrophages are professional phagocytic cells of the hematopoietic system specializing in the detection, phagocytosis and destruction of bacteria and other harmful micro-organisms, apoptotic cells and metabolic byproducts.

Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression.

Glioblastoma (GBM) is an incurable primary malignant brain cancer hallmarked with a substantial protumorigenic immune component. Knowledge of the GBM immune microenvironment during tumor evolution and standard of care treatments is limited. Using single-cell transcriptomics and flow cytometry, we unveiled large-scale comprehensive longitudinal changes in immune cell composition throughout tumor progression in an epidermal growth factor receptor-driven genetic mouse GBM model.

Effects of PD-1 Signaling on Immunometabolic Reprogramming.

Programmed Death-1 (PD-1; CD279) is an inhibitory receptor induced in several activated immune cells and, after engagement with its ligands PD-L1 and PD-L2, serves as a key mediator of peripheral tolerance. However, PD-1 signaling also has detrimental effects on T cell function by posing breaks on antitumor and antiviral immunity. PD-1 blocking immunotherapy either alone or in combination with other therapeutic modalities has shown great promise in cancer treatment.

Flow Cytometric Analysis for Identification of the Innate and Adaptive Immune Cells of Murine Lung.

The respiratory tract is in direct contact with the outside environment and requires a precisely regulated immune system to provide protection while suppressing unwanted reactions to environmental antigens. Lungs host several populations of innate and adaptive immune cells that provide immune surveillance but also mediate protective immune responses. These cells, which keep the healthy pulmonary immune system in balance, also participate in several pathological conditions such as asthma, infections, autoimmune diseases, and cancer.

The PD-1 Interactome.

T cell activation is a fine-tuned process that involves T cell receptor and costimulation signals. To prevent undue activation of T cells, inhibitory molecules including PD-1 (programmed death 1) are induced and function as brakes for T cell signaling. In a steady state, the interaction of PD-1 with its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273) maintains peripheral immune tolerance.

Commentary on: Combination of Metabolic Intervention and T Cell Therapy Enhances Solid Tumor Immunotherapy.

Metabolism is a common cellular feature. Cancer creates a suppressive microenvironment resulting in inactivation of antigen-specific T cells by metabolic reprogramming. Development of approaches that enhance and sustain physiologic properties of T cell metabolism to prevent T cell inactivation and promote effector function in the tumor microenvironment is an urgent need for improvement of cell-based cancer immunotherapies.

Blockade of 6-phosphogluconate dehydrogenase generates CD8 effector T cells with enhanced anti-tumor function.

Although T cell expansion depends on glycolysis, T effector cell differentiation requires signaling via the production of reactive oxygen species (ROS). Because the pentose phosphate pathway (PPP) regulates ROS by generating nicotinamide adenine dinucleotide phosphate (NADPH), we examined how PPP blockade affects T cell differentiation and function. Here, we show that genetic ablation or pharmacologic inhibition of the PPP enzyme 6-phosphogluconate dehydrogenase (6PGD) in the oxidative PPP results in the generation of superior CD8 T effector cells.

PD-1 T cells: a foe in cancer immunotherapy?

The mechanisms that drive responses to PD-1-blocking immunotherapy in some but not all patients have been puzzling. A new study suggests that the balance of PD-1 expression levels between CD8 T cells and T cells might provide an answer.