Coinhibitory receptors, such as CTLA-4 and PD-1, play a critical role in maintaining immune homeostasis by dampening T cell responses. Recently, they have gained attention as therapeutic targets in ...chronic disease settings where their dysregulated expression contributes to suppressed immune responses. The novel coinhibitory receptor TIGIT (T cell Ig and ITIM domain) has been shown to play an important role in modulating immune responses in the context of autoimmunity and cancer. However, the molecular mechanisms by which TIGIT modulates immune responses are still insufficiently understood. We have generated a panel of monoclonal anti-mouse TIGIT Abs that show functional properties in mice in vivo and can serve as important tools to study the underlying mechanisms of TIGIT function. We have identified agonistic as well as blocking anti-TIGIT Ab clones that are capable of modulating T cell responses in vivo. Administration of either agonist or blocking anti-TIGIT Abs modulated autoimmune disease severity whereas administration of blocking anti-TIGIT Abs synergized with anti-PD-1 Abs to affect partial or even complete tumor regression. The Abs presented in this study can thus serve as important tools for detailed analysis of TIGIT function in different disease settings and the knowledge gained will provide valuable insight for the development of novel therapeutic approaches targeting TIGIT.
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.
Knockout (KO) mouse models play critical roles in elucidating biological processes behind disease-associated or disease-resistant traits. As a presumed consequence of gene KO, mice display certain ...phenotypes. Based on insight into the molecular role of said gene in a biological process, it is inferred that the particular biological process causally underlies the trait. This approach has been crucial towards understanding the basis of pathological and/or advantageous traits associated with
KO mice.
KO mice suffer from severe, early-onset retinal degeneration. MERTK, expressed in retinal pigment epithelia, is a receptor tyrosine kinase with a critical role in phagocytosis of apoptotic cells or cellular debris. Therefore, early-onset, severe retinal degeneration was described to be a direct consequence of failed MERTK-mediated phagocytosis of photoreceptor outer segments by retinal pigment epithelia. Here, we report that the loss of
alone is not sufficient for retinal degeneration. The widely used
KO mouse carries multiple coincidental changes in its genome that affect the expression of a number of genes, including the
paralog
. Retinal degeneration manifests only when the function of
is concomitantly lost. Furthermore,
KO mice display improved anti-tumor immunity. MERTK is expressed in macrophages. Therefore, enhanced anti-tumor immunity was inferred to result from the failure of macrophages to dispose of cancer cell corpses, resulting in a pro-inflammatory tumor microenvironment. The resistance against two syngeneic mouse tumor models observed in
KO mice is not, however, phenocopied by the loss of
alone. Neither
nor macrophage phagocytosis by alternate genetic redundancy accounts for the absence of anti-tumor immunity. Collectively, our results indicate that context-dependent epistasis of independent modifier alleles determines
KO traits.
Sympathetic nerves that innervate lymphoid organs regulate immune development and function by releasing norepinephrine that is sensed by immune cells via their expression of adrenergic receptors. ...Here, we demonstrate that ablation of sympathetic nervous system (SNS) signaling suppresses tumor immunity, and we dissect the mechanism of such immune suppression. We report that disruption of the SNS in mice removes a critical α-adrenergic signal required for maturation of myeloid cells in normal and tumor-bearing mice. In tumor-bearing mice, disruption of the α-adrenergic signal leads to the accumulation of immature myeloid-derived suppressor cells (MDSCs) that suppress tumor immunity and promote tumor growth. Furthermore, we show that these SNS-responsive MDSCs drive expansion of regulatory T cells via secretion of the alarmin heterodimer S100A8/A9, thereby compounding their immunosuppressive activity. Our results describe a regulatory framework in which sympathetic tone controls the development of innate and adaptive immune cells and influences their activity in health and disease.
Outcomes following the excision of the external iliac vein during gynaecological oncology surgery are poorly documented. This is because most gynaecological oncologists consider tumours with vascular ...involvement inoperable. We describe a patient whose right external iliac vein was transected during the removal of a large broad ligament leiomyosarcoma invading the right external iliac vein. The patient's recovery following surgery was uneventful, and she remained disease-free 6 months postoperatively, with minimal morbidity. In describing this case, we hope to educate and inform other gynaecological oncologists facing a similar surgical challenge. We also propose that resection of the external iliac vessels in such cases is safe and feasible, and summarise the anatomical course of venous collaterals, which develop when the external iliac veins are obstructed.
•Cancers invading the external iliac veins are not a limitation for surgery.•Our case demonstrates the feasibility of en bloc resection of these pelvic tumours.•In cases of pelvic venous obstruction, existing collaterals can be activated to drain the lower limbs.•Complete resection to achieve negative tumour margins is safe and feasible.•Advances in imaging allow meticulous preoperative planning and patient counselling.
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.
Abstract
Complex networks are a powerful way to reason about systems with non-trivial patterns of interaction. The increased attention in this research area is accelerated by the increasing ...availability of complex network data sets, with data often being reused as secondary data sources. Typically, multiple data sources are combined to create a larger, fuller picture of these complex networks and in doing so scientists have to make sometimes subjective decisions about how these sources should be integrated. These seemingly trivial decisions can sometimes have significant impact on both the resultant integrated networks and any downstream network models executed on them. We highlight the importance of this impact in online social networks and dark networks, two use-cases where data are regularly combined from multiple sources due to challenges in measurement or overlap of networks. We present a method for systematically testing how different, realistic data integration approaches can alter both the networks themselves and network models run on them, as well as an associated Python package (NIDMod) that implements this method. A number of experiments show the effectiveness of our method in identifying the impact of different data integration setups on network diffusion models.
Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients ...and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8+ tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and we use CRISPR-Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8+ TILs. Our results open novel avenues for targeting dysfunctional T cell states while leaving activation programs intact.
Display omitted
•Distinct gene modules for T cell dysfunction and activation can be uncoupled•Single-cell profiling of CD8 TILs shows that these modules are exclusive•Metallothioneins, zinc regulators, promote T cell dysfunction•CRISPR-Cas9 targeting shows Gata-3, a zinc-finger TF, promotes dysfunction
Single-cell profiling of tumor-infiltrating lymphocytes identifies critical regulators of T cell dysfunction in cancer, opening new avenues for targeting dysfunctional T cell states while leaving activation programs intact.
To assess the impact of 5 or more cycles of neoadjuvant chemotherapy (NACT) and cytoreductive outcomes on overall survival (OS) in patients undergoing interval debulking surgery (IDS) for advanced ...ovarian cancer.
A retrospective review of patients receiving NACT followed by IDS between 2007 and 2017. Patients were analysed according to number of NACT cycles received: group 1 consisted of patients receiving ≤4 cycles and group 2 consisted of those receiving ≥5 cycles. Outcomes were stratified by cytoreductive outcome, surgical complexity, stage and chemotherapy exposure.
231 patients in group 1 and 167 in group 2 were identified. In group 1, the OS for those achieving Complete (R0), Optimal<1 cm (R1) and Suboptimal (R2) was 51.1, 36.1, and 34.3 months respectively. Statistically significant differences in survival were seen in patients achieving R0vR2 (p < 0.019) but not in R0vR1 (p = 0.125) or R1vR2 (p = 0.358). In group 2, the OS for those achieving R0, R1 and R2 was 53.0, 24.7, and 22.1 months respectively. Statistically significant differences were seen between R0vR1 and R0vR2 (p < 0.00001) but not between R1vR2 (p = 0.917). No difference in OS was seen between groups 1 and 2. In patients achieving R1, there was a trend towards decreasing OS with increasing exposure to NACT from 36.1 (95%CI 32.0–40.2)months with 3 cycles to 24.3 (95%CI 14.4–34.2)months with ≥6 cycles.
Surgery with utilisation of cytoreductive procedures to achieve complete clearance should be offered to all patients even after ≥5 cycles if R0 can be achieved. R1 cytoreduction has questionable value in those receiving ≤4 cycles and no value in those receiving ≥5 cycles.
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