The blockade of immune checkpoint receptors has made great strides in the treatment of major cancers, including melanoma, Hodgkin’s lymphoma, renal, and lung cancer. However, the success rate of ...immune checkpoint blockade is still low and some cancers, such as microsatellite‐stable colorectal cancer, remain refractory to these treatments. This has prompted investigation into additional checkpoint receptors. T-cell immunoglobulin and mucin domain 3 (Tim-3) is a checkpoint receptor expressed by a wide variety of immune cells as well as leukemic stem cells. Coblockade of Tim-3 and PD-1 can result in reduced tumor progression in preclinical models and can improve antitumor T-cell responses in cancer patients. In this review, we will discuss the basic biology of Tim-3, its role in the tumor microenvironment, and the emerging clinical trial data that point to its future application in the field of immune-oncology.
Both in vivo data in preclinical cancer models and in vitro data with T cells from patients with advanced cancer support a role for Tim-3 blockade in promoting effective anti-tumor immunity. ...Consequently, there is considerable interest in the clinical development of antibody-based therapeutics that target Tim-3 for cancer immunotherapy. A challenge to this clinical development is the fact that several ligands for Tim-3 have been identified: galectin-9, phosphatidylserine, HMGB1, and most recently, CEACAM1. These observations raise the important question of which of these multiple receptor:ligand relationships must be blocked by an anti-Tim-3 antibody in order to achieve therapeutic efficacy. Here, we have examined the properties of anti-murine and anti-human Tim-3 antibodies that have shown functional efficacy and find that all antibodies bind to Tim-3 in a manner that interferes with Tim-3 binding to both phosphatidylserine and CEACAM1. Our data have implications for the understanding of Tim-3 biology and for the screening of anti-Tim-3 antibody candidates that will have functional properties in vivo.
Abstract
Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipids. Endogenous intestinal cannabinoids such as Anandamide, control appetite and ...energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we show that Anandamide and its vanilloid receptor, VR1, mediate immune homeostasis in the gut and pancreas. Capsaicin, a vanilloid, with which Anandamide shares VR1, acts similarly. Engagement of the cannabinoid/vanilloid receptor augments the number and immune suppressive function of the regulatory CX3CR1hi macrophages, which express the highest levels of such receptors among the gut immune cells. Additionally, mice that are genetically deficient in VR1 have reduced proportions of CX3CR1hi macrophages in the gut. Treatment of mice with capsaicin also leads to differentiation of a regulatory subset of CD4+ T cells called Tr1 cells in an IL27 dependent manner both in vitro and in vivo. In a functional demonstration, tolerance elicited by engagement of VR1 can be transferred to naïve NOD mice (model of type 1 diabetes) by transfer of CD4+ T cells. Our study unveils a novel role for cannabinoids in maintaining immune homeostasis in the gut/pancreas, and reveals a new conversation between the nervous and immune systems, using distinct receptors.
Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid. Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and ...energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we uncover a role for AEA and its receptor, cannabinoid receptor 2 (CB2), in the regulation of immune tolerance in the gut and the pancreas. This work demonstrates a major immunological role for an endocannabinoid. The pungent molecule capsaicin (CP) has a similar effect as AEA; however, CP acts by engagement of the vanilloid receptor TRPV1, causing local production of AEA, which acts through CB2. We show that the engagement of the cannabinoid/vanilloid receptors augments the number and immune suppressive function of the regulatory CX3CR1hi macrophages (Mϕ), which express the highest levels of such receptors among the gut immune cells. Additionally, TRPV1−/− or CB2−/− mice have fewer CX3CR1hi Mϕ in the gut. Treatment of mice with CP also leads to differentiation of a regulatory subset of CD4⁺ cells, the Tr1 cells, in an IL-27–dependent manner in vitro and in vivo. In a functional demonstration, tolerance elicited by engagement of TRPV1 can be transferred to naïve nonobese diabetic (NOD) mice model of type 1 diabetes (T1D) by transfer of CD4⁺ T cells. Further, oral administration of AEA to NOD mice provides protection from T1D. Our study unveils a role for the endocannabinoid system in maintaining immune homeostasis in the gut/pancreas and reveals a conversation between the nervous and immune systems using distinct receptors.
New Clones on the Block Acharya, Nandini; Anderson, Ana C.
Immunity (Cambridge, Mass.),
10/2019, Letnik:
51, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Although immune checkpoint blockade (ICB) has yielded striking clinical responses in subsets of cancer patients, the mechanism of action is still unclear. In a recent issue of Nature Medicine, Yost ...et al., 2019 report that the T cell clones that dominate the intra-tumoral T cell landscape after ICB are distinct from those prior to treatment, a phenomenon referred to by the authors as “clonal replacement.”
Although immune checkpoint blockade (ICB) has yielded striking clinical responses in subsets of cancer patients, the mechanism of action is still unclear. In a recent issue of Nature Medicine, Yost et al., 2019 report that the T cell clones that dominate the intra-tumoral T cell landscape after ICB are distinct from those prior to treatment, a phenomenon referred to by the authors as “clonal replacement.”
The expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated expression of co-inhibitory receptors on CD4
T ...cells promotes autoimmunity, whereas sustained overexpression on CD8
T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and diseases such as cancer
. Here, using RNA and protein expression profiling at single-cell resolution in mouse cells, we identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, TIM-3, LAG-3 and TIGIT) but also many new surface receptors. We functionally validated two new co-inhibitory receptors, activated protein C receptor (PROCR) and podoplanin (PDPN). The module of co-inhibitory receptors is co-expressed in both CD4
and CD8
T cells and is part of a larger co-inhibitory gene program that is shared by non-responsive T cells in several physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors PRDM1 and c-MAF as cooperative regulators of the co-inhibitory module, and this was validated experimentally. This molecular circuit underlies the co-expression of co-inhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumour immunity.
Identifying signals in the tumor microenvironment (TME) that shape CD8+ T cell phenotype can inform novel therapeutic approaches for cancer. Here, we identified a gradient of increasing ...glucocorticoid receptor (GR) expression and signaling from naïve to dysfunctional CD8+ tumor-infiltrating lymphocytes (TILs). Conditional deletion of the GR in CD8+ TILs improved effector differentiation, reduced expression of the transcription factor TCF-1, and inhibited the dysfunctional phenotype, culminating in tumor growth inhibition. GR signaling transactivated the expression of multiple checkpoint receptors and promoted the induction of dysfunction-associated genes upon T cell activation. In the TME, monocyte-macrophage lineage cells produced glucocorticoids and genetic ablation of steroidogenesis in these cells as well as localized pharmacologic inhibition of glucocorticoid biosynthesis improved tumor growth control. Active glucocorticoid signaling associated with failure to respond to checkpoint blockade in both preclinical models and melanoma patients. Thus, endogenous steroid hormone signaling in CD8+ TILs promotes dysfunction, with important implications for cancer immunotherapy.
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•Endogenous glucocorticoid signaling shapes CD8+ T cell differentiation in tumors•The glucocorticoid receptor transactivates IL-10 and checkpoint receptor expression•Tumor monocyte-macrophage lineage cells produce glucocorticoid•Glucocorticoid signaling in CD8+ T cells reduces immune checkpoint blockade efficacy
Acharya et al. uncover a gradient of increasing glucocorticoid signaling from naïve to dysfunctional CD8+ tumor-infiltrating lymphocytes. This gradient regulates effector transition and development of dysfunction. Glucocorticoid is produced locally by tumor-associated monocyte-macrophage lineage cells, and presence of active glucocorticoid signaling associates with poor response to immune checkpoint blockade.
Abstract
We have previously reported that oral administration of Capsaicin (CP), the pungent component of chili peppers inhibits proliferation and activation of auto-reactive T cells and protects ...mice from development of Type-1 diabetes (T1D) in a dose dependent manner. Here, we demonstrate that orally administered CP leads to induction of CX3CR1+ macrophages specifically in lamina propria and in the pancreatic lymph nodes. CX3CR1+ macrophages also known as regulatory macrophages (Mregs) play a critical role in maintenance of immune homeostasis in the gut. Inflammation hampers the differentiation of monocytes into CX3CR1+ macrophages in the gut. However, the factors responsible for facilitating the differentiation into Mregs remain elusive. Using mice deficient in Vanilloid Receptor 1 (VR1), the receptor for CP, we report that VR1 is important for the differentiation of macrophages into Mregs, which subsequently play a key role in tolerance induction via the induction of immune-suppressive CD4+IL10+FoxP3- Tr1 cells. This process culminates in providing protection from T1D in NOD mice. This study elucidates how a common food additive, CP, can act as a potent immune-modulatory agent and ameliorate autoimmune disease like T1D.
Abstract
VR1 is a non-selective cation channel, highly expressed by sensory neurons and cells of the immune system e.g. dendritic cells (DCs) and macrophages. Capsaicin (CP), the pungent component of ...chili peppers is a chemical ligand of VR1. We have recently reported that oral administration of CP inhibits proliferation and activation of auto-reactive T cells and protects mice from development of Type-1 diabetes (T1D) in a dose dependent manner. Here we demonstrate that orally administered CP can lead to an increase in IL-27 producing DCs, and IL10 producing CD4+/FoxP3- T cells (Tr1) but decrease in the frequency of CD4+/IL17+ T cells (TH17) in the pancreatic lymph node (PLN). We also demonstrate that splenocytes and PLN cells when adoptively transferred from capsaicin fed mouse to a naïve NOD mouse leads to protection of the recipient mouse from T1D. Our results thus demonstrate that engagement of VR1 on immune cells can have profound effect on gut mediated immune tolerance and autoimmunity.
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