Tumor-associated macrophages (TAMs) promote metastasis and inhibit T cells, but macrophages can be polarized to kill cancer cells. Macrophage polarization could thus be a strategy for controlling ...cancer. We show that macrophages from metastatic pleural effusions of breast cancer patients can be polarized to kill cancer cells with monophosphoryl lipid A (MPLA) and interferon (IFN) γ. MPLA + IFNγ injected intratumorally or intraperitoneally reduces primary tumor growth and metastasis in breast cancer mouse models, suppresses metastasis, and enhances chemotherapy response in an ovarian cancer model. Both macrophages and T cells are critical for the treatment's anti-metastatic effects. MPLA + IFNγ stimulates type I IFN signaling, reprograms CD206+ TAMs to inducible NO synthase (iNOS)+ macrophages, and activates cytotoxic T cells through macrophage-secreted interleukin-12 (IL-12) and tumor necrosis factor alpha (TNFα). MPLA and IFNγ are used individually in clinical practice and together represent a previously unexplored approach for engaging a systemic anti-tumor immune response.
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•MPLA + IFNγ repolarizes TAMs from mice and patients to tumoricidal macrophages•MPLA + IFNγ activates cytotoxic T cells through macrophage-secreted IL-12 and TNFα•MPLA + IFNγ suppresses tumor growth and metastasis in breast and ovarian cancer models•MPLA + IFNγ enhances the response to chemotherapy in ovarian cancer
Sun et al. combine monophosphoryl lipid A (MPLA) with interferon γ (IFNγ) to reprogram macrophages, activate cytotoxic T cells, suppress tumor growth and metastasis, and enhance chemotherapy response in mice. MPLA and IFNγ are used individually in clinical practice and together represent a previously unexplored approach for eliciting anti-metastatic responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Neonatal CD4
+
and CD8
+
T cells have historically been characterized as immature or defective. However, recent studies prompt a reinterpretation of the functions of neonatal T cells. Rather than a ...population of cells always falling short of expectations set by their adult counterparts, neonatal T cells are gaining recognition as a distinct population of lymphocytes well suited for the rapidly changing environment in early life. In this review, I will highlight new evidence indicating that neonatal T cells are not inert or less potent versions of adult T cells but instead are a broadly reactive layer of T cells poised to quickly develop into regulatory or effector cells, depending on the needs of the host. In this way, neonatal T cells are well adapted to provide fast-acting immune protection against foreign pathogens, while also sustaining tolerance to self-antigens.
Cytotoxic T cells infiltrating tumors are thought to utilize HIF transcription factors during adaptation to the hypoxic tumor microenvironment. Deletion analyses of the two key HIF isoforms found ...that HIF-1α, but not HIF-2α, was essential for the effector state in CD8+ T cells. Furthermore, loss of HIF-1α in CD8+ T cells reduced tumor infiltration and tumor cell killing, and altered tumor vascularization. Deletion of VEGF-A, an HIF target gene, in CD8+ T cells accelerated tumorigenesis while also altering vascularization. Analyses of human breast cancer showed inverse correlations between VEGF-A expression and CD8+ T cell infiltration, and a link between T cell infiltration and vascularization. These data demonstrate that the HIF-1α/VEGF-A axis is an essential aspect of tumor immunity.
•HIF-1α drives CD8+ T cell migration and effector function•HIF-1α loss in T cells accelerates tumor growth•Loss of VEGF-A in T cells accelerates tumor growth•Loss of VEGF-A in T cells results in increased chemotherapeutic response
Palazon et al. demonstrate the importance of the HIF-1α/VEGF-A axis in tumor immunity. HIF-1α, but not HIF-2α, drives CD8+ T cell glycolytic metabolism, migration, and effector function, while the HIF-1α transcriptional target VEGF-A contributes to tumor vascularization.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background IgG4 -related disease (IgG4 -RD) is a systemic condition of unknown cause characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates. CD4+ T cells constitute the ...major inflammatory cell population in IgG4 -RD lesions. Objective We used an unbiased approach to characterize CD4+ T-cell subsets in patients with IgG4 -RD based on their clonal expansion and ability to infiltrate affected tissue sites. Methods We used flow cytometry to identify CD4+ effector/memory T cells in a cohort of 101 patients with IgG4 -RD. These expanded cells were characterized by means of gene expression analysis and flow cytometry. Next-generation sequencing of the T-cell receptor β chain gene was performed on CD4+ SLAMF7+ cytotoxic T lymphocytes (CTLs) and CD4+ GATA3+ TH 2 cells in a subset of patients to identify their clonality. Tissue infiltration by specific T cells was examined by using quantitative multicolor imaging. Results CD4+ effector/memory T cells with a cytolytic phenotype were expanded in patients with IgG4 -RD. Next-generation sequencing revealed prominent clonal expansions of these CD4+ CTLs but not CD4+ GATA3+ memory TH 2 cells in patients with IgG4 -RD. The dominant T cells infiltrating a range of inflamed IgG4 -RD tissue sites were clonally expanded CD4+ CTLs that expressed SLAMF7, granzyme A, IL-1β, and TGF-β1. Clinical remission induced by rituximab-mediated B-cell depletion was associated with a reduction in numbers of disease-associated CD4+ CTLs. Conclusions IgG4 -RD is prominently linked to clonally expanded IL-1β– and TGF-β1–secreting CD4+ CTLs in both peripheral blood and inflammatory tissue lesions. These active, terminally differentiated, cytokine-secreting effector CD4+ T cells are now linked to a human disease characterized by chronic inflammation and fibrosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Cancer immunotherapy shows limited efficacy against many solid tumors that originate from epithelial tissues, including triple-negative breast cancer (TNBC). We identify the SOX4 transcription factor ...as an important resistance mechanism to T cell-mediated cytotoxicity for TNBC cells. Mechanistic studies demonstrate that inactivation of SOX4 in tumor cells increases the expression of genes in a number of innate and adaptive immune pathways important for protective tumor immunity. Expression of SOX4 is regulated by the integrin αvβ6 receptor on the surface of tumor cells, which activates TGFβ from a latent precursor. An integrin αvβ6/8-blocking monoclonal antibody (mAb) inhibits SOX4 expression and sensitizes TNBC cells to cytotoxic T cells. This integrin mAb induces a substantial survival benefit in highly metastatic murine TNBC models poorly responsive to PD-1 blockade. Targeting of the integrin αvβ6-TGFβ–SOX4 pathway therefore provides therapeutic opportunities for TNBC and other highly aggressive human cancers of epithelial origin.
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•The SOX4 transcription factor induces tumor cell resistance to cytotoxic T cells•SOX4 inhibits expression of genes in innate and adaptive immune pathways•SOX4 expression can be inhibited with an integrin αvβ6-blocking antibody•Antibody treatment results in a substantial survival benefit in models of TNBC
Bagati et al. show that the SOX4 transcription factor induces tumor cell resistance to cytotoxic T cells. Integrin αvβ6 on the surface of epithelial cancer cells activates TGFβ from a latent precursor to induce SOX4 expression, and antibody-mediated inhibition of integrin αvβ6 induces T cell-mediated immunity in immunotherapy-resistant tumor models.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Senescent cells play relevant but context-dependent roles during tumorigenesis. Here, in an oncogenic Kras-driven lung cancer mouse model, we found that senescent cells, specifically alveolar ...macrophages, accumulate early in neoplasia. These macrophages have upregulated expression of p16INK4a and Cxcr1, are distinct from previously defined subsets and are sensitive to senolytic interventions, and suppress cytotoxic T cell responses. Their removal attenuates adenoma development and progression in mice, indicating their tumorigenesis-promoting role. Importantly, we found that alveolar macrophages with these properties increase with normal aging in mouse lung and in human lung adenocarcinoma in situ. Collectively, our study indicates that a subset of tissue-resident macrophages can support neoplastic transformation through altering their local microenvironment, suggesting that therapeutic interventions targeting senescent macrophages may attenuate lung cancer progression during early stages of disease.
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•Senescent cells accelerate spontaneous KrasLA1-driven lung tumorigenesis•Senescent alveolar macrophages accumulate in aged and tumorous tissue•Surprisingly, knocking out p16INK4a or p21Cip1 delays neoplasia in KrasLA1 mice•Senescent alveolar macrophages counteract cytotoxic T cell accumulation
Prieto et al. causally implicate the cellular senescence program in the innate component of the immune system. Senescent alveolar macrophages with tumor-promoting qualities accumulate early in Kras-driven neoplasia, promoting tumorigenesis by adjusting the antitumor T cell response. These senescent macrophages also accumulate with natural age and occur in human NSCLC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Local environmental factors influence CD8+ T cell priming in lymph nodes (LNs). Here, we sought to understand how factors unique to the tumor-draining mediastinal LN (mLN) impact CD8+ T cell ...responses toward lung cancer. Type 1 conventional dendritic cells (DC1s) showed a mLN-specific failure to induce robust cytotoxic T cells responses. Using regulatory T (Treg) cell depletion strategies, we found that Treg cells suppressed DC1s in a spatially coordinated manner within tissue-specific microniches within the mLN. Treg cell suppression required MHC II-dependent contact between DC1s and Treg cells. Elevated levels of IFN-γ drove differentiation Treg cells into Th1-like effector Treg cells in the mLN. In patients with cancer, Treg cell Th1 polarization, but not CD8+/Treg cell ratios, correlated with poor responses to checkpoint blockade immunotherapy. Thus, IFN-γ in the mLN skews Treg cells to be Th1-like effector Treg cells, driving their close interaction with DC1s and subsequent suppression of cytotoxic T cell responses.
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•Lung LN-specific enrichment in IFN-γ induces suppressive Th1-like effector Treg cells•LN microniches skew Treg cells to be Th1-like and drive DC1 suppression•Suppressed DC1s prime dysfunctional CD8+ T cell responses against lung cancer•IFN-γ blockade repolarizes Treg cells and restores CTL priming against lung cancer
How tissue-specific mechanisms shape anti-tumor immunity remains poorly understood. Zagorulya et al. reveal that lung lymph node (LN)-specific abundance of interferon-gamma induces suppressive Th1-like effector regulatory T (Treg) cells. These effector Treg cells interact with type 1 conventional dendritic cells and restrain priming of cytotoxic T cell responses against lung cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Inflammatory disorders of the CNS are frequently accompanied by synaptic loss, which is thought to involve phagocytic microglia and complement components. However, the mechanisms accounting for ...aberrant synaptic connectivity in the context of CD8+ T cell-driven neuronal damage are poorly understood. Here, we profiled the neuronal translatome in a murine model of encephalitis caused by CD8+ T cells targeting antigenic neurons. Neuronal STAT1 signaling and downstream CCL2 expression were essential for apposition of phagocytes, ensuing synaptic loss and neurological disease. Analogous observations were made in the brains of Rasmussen’s encephalitis patients. In this devastating CD8+ T cell-driven autoimmune disease, neuronal STAT1 phosphorylation and CCL2 expression co-clustered with infiltrating CD8+ T cells as well as phagocytes. Taken together, our findings uncover an active role of neurons in coordinating phagocyte-mediated synaptic loss and highlight neuronal STAT1 and CCL2 as critical steps in this process that are amenable to pharmacological interventions.
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•Neuronal translatome during CD8+ T cell attack reveals disease-associated pathways•Neuronally induced STAT1 and downstream CCL2 drive phagocyte-mediated synaptic loss•STAT1/CCL2 signature is conserved in murine and human neuroinflammatory diseases•Neuronal STAT1/CCL2 signaling blockade prevents synaptic stripping and disease
Neurons act as intermediaries between CD8+ T cells and phagocytes, driving their own synaptic loss during neuroinflammation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The gut microbiota contributes to the development of normal immunity but, when dysregulated, can promote autoimmunity through various non-antigen-specific effects on pathogenic and regulatory ...lymphocytes. Here, we show that an integrase expressed by several species of the gut microbial genus Bacteroides encodes a low-avidity mimotope of the pancreatic β cell autoantigen islet-specific glucose-6-phosphatase-catalytic-subunit-related protein (IGRP206-214). Studies in germ-free mice monocolonized with integrase-competent, integrase-deficient, and integrase-transgenic Bacteroides demonstrate that the microbial epitope promotes the recruitment of diabetogenic CD8+ T cells to the gut. There, these effectors suppress colitis by targeting microbial antigen-loaded, antigen-presenting cells in an integrin β7-, perforin-, and major histocompatibility complex class I-dependent manner. Like their murine counterparts, human peripheral blood T cells also recognize Bacteroides integrase. These data suggest that gut microbial antigen-specific cytotoxic T cells may have therapeutic value in inflammatory bowel disease and unearth molecular mimicry as a novel mechanism by which the gut microbiota can regulate normal immune homeostasis.
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•The Bacteroides integrase encodes a low-avidity mimotope of IGRP206-214•The microbial epitope recruits diabetogenic CD8+ T cells to the gut•Crossreactive CD8+ T cells suppress colitis by targeting gut DCs•Suppression of colitis is MHC class I-, Itgb7-, and perforin-dependent
A microbiome-generated molecule that acts as a molecular mimic of a human disease-linked autoantigen is surprisingly protective against host colitis and may be more broadly involved in maintaining gut immune homeostasis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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