PD-1+ natural killer cells in human non-small cell lung cancer can be activated by PD-1/PD-L1 blockade

Natural killer (NK) cells are critically involved in anti-tumor immunity by targeting tumor cells. In this study, we show that intratumoral NK cells from NSCLC patients expressed elevated levels of the immune checkpoint receptor PD-1 on their cell surface. In contrast to the expression of activating receptors, PD-1; +; NK cells co-expressed more inhibitory receptors compared to PD-1; -; NK cells. Intratumoral NK cells were less functional compared to peripheral NK cells, and this dysfunction correlated with PD-1 expression. Tumor cells expressing PD-L1 inhibited the functionality of PD-1; +; NK cells in ex vivo models and induced PD-1 clustering at the immunological synapse between NK cells and tumor cells. Notably, treatment with PD-1 blockade was able to reverse PD-L1-mediated inhibition of PD-1; +; NK cells. Our findings highlight the therapeutic potential of PD-1; +; NK cells in immune checkpoint blockade and could guide the development of NK cell-stimulating agents in combination with PD-1 blockade

NK cells with tissue-resident traits shape response to immunotherapy by inducing adaptive antitumor immunity

T cell-directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen the clinical benefit of immunotherapies. Here, we demonstrate that therapeutic targeting of the interferon-γ (IFN-γ)-interleukin-12 (IL-12) pathway relies on the ability of a population of natural killer (NK) cells with tissue-resident traits to orchestrate an antitumor microenvironment. In particular, we used an engineered adenoviral platform as a tool for intratumoral IL-12 immunotherapy (AdV5-IL-12) to generate adaptive antitumor immunity. Mechanistically, we demonstrate that AdV5-IL-12 is capable of inducing the expression of CC-chemokine ligand 5 (CCL5) in CD49a+ NK cells both in tumor mouse models and tumor specimens from patients with cancer. AdV5-IL-12 imposed CCL5-induced type I conventional dendritic cell (cDC1) infiltration and thus increased DC-CD8 T cell interactions. A similar observation was made for other IFN-γ-inducing therapies such as Programmed cell death 1 (PD-1) blockade. Conversely, failure to respond to IL-12 and PD-1 blockade in tumor models with low CD49a+ CXCR6+ NK cell infiltration could be overcome by intratumoral delivery of CCL5. Thus, therapeutic efficacy depends on the abundance of NK cells with tissue-resident traits and, specifically, their capacity to produce the DC chemoattractant CCL5. Our findings reveal a barrier for T cell-focused therapies and offer mechanistic insights into how T cell-NK cell-DC cross-talk can be enhanced to promote antitumor immunity and overcome resistance

NK cells with tissue-resident traits shape response to immunotherapy by inducing adaptive antitumor immunity

T cell-directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen the clinical benefit of immunotherapies. Here, we demonstrate that therapeutic targeting of the interferon-γ (IFN-γ)-interleukin-12 (IL-12) pathway relies on the ability of a population of natural killer (NK) cells with tissue-resident traits to orchestrate an antitumor microenvironment. In particular, we used an engineered adenoviral platform as a tool for intratumoral IL-12 immunotherapy (AdV5-IL-12) to generate adaptive antitumor immunity. Mechanistically, we demonstrate that AdV5-IL-12 is capable of inducing the expression of CC-chemokine ligand 5 (CCL5) in CD49a; +; NK cells both in tumor mouse models and tumor specimens from patients with cancer. AdV5-IL-12 imposed CCL5-induced type I conventional dendritic cell (cDC1) infiltration and thus increased DC-CD8 T cell interactions. A similar observation was made for other IFN-γ-inducing therapies such as Programmed cell death 1 (PD-1) blockade. Conversely, failure to respond to IL-12 and PD-1 blockade in tumor models with low CD49a; +; CXCR6; +; NK cell infiltration could be overcome by intratumoral delivery of CCL5. Thus, therapeutic efficacy depends on the abundance of NK cells with tissue-resident traits and, specifically, their capacity to produce the DC chemoattractant CCL5. Our findings reveal a barrier for T cell-focused therapies and offer mechanistic insights into how T cell-NK cell-DC cross-talk can be enhanced to promote antitumor immunity and overcome resistance

Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells

© 2018, American Society for Clinical Investigation. This article has been published in final form at https://doi.org/10.1172/JCI120612First-generation immune checkpoint inhibitors, including anti-CTLA-4 and anti-programmed death 1 (anti-PD-1) antibodies, have led to major clinical progress, yet resistance frequently leads to treatment failure. Thus, new targets acting on T cells are needed. CD33-related sialic acid-binding immunoglobulin-like lectins (Siglecs) are pattern-recognition immune receptors binding to a range of sialoglycan ligands, which appear to function as self-associated molecular patterns (SAMPs) that suppress autoimmune responses. Siglecs are expressed at very low levels on normal T cells, and these receptors were not until recently considered as interesting targets on T cells for cancer immunotherapy. Here, we show an upregulation of Siglecs, including Siglec-9, on tumor-infiltrating T cells from non-small cell lung cancer (NSCLC), colorectal, and ovarian cancer patients. Siglec-9-expressing T cells coexpressed several inhibitory receptors, including PD-1. Targeting of the sialoglycan-SAMP/Siglec pathway in vitro and in vivo resulted in increased anticancer immunity. T cell expression of Siglec-9 in NSCLC patients correlated with reduced survival, and Siglec-9 polymorphisms showed association with the risk of developing lung and colorectal cancer. Our data identify the sialoglycan-SAMP/Siglec pathway as a potential target for improving T cell activation for immunotherapy.Peer reviewe

Targeting sialic acid-Siglec interactions to reverse immune suppression in cancer.

Changes in sialic acids in cancer have been observed for many years. In particular, the increase of sialoglycan density or hypersialylation in tumors has been described. Recent studies have identified mechanisms for immune evasion based on sialoglycan interactions with immunoregulatory Siglec receptors that are exploited by tumor cells and microorganisms alike. Siglecs are mostly inhibitory receptors similar to known immune checkpoints including PD-1 or CTLA-4 that are successfully targeted with blocking antibodies for cancer immunotherapy. Here, we summarize the known changes of sialic acids in cancer and the role Siglec receptors play in cancer immunity. We also focus on potential ways to target these Siglec receptors or sialoglycans in order to improve anti-cancer immunity

Targeting sialic acid-Siglec interactions to reverse immune suppression in cancer

Changes in sialic acids in cancer have been observed for many years. In particular, the increase of sialoglycan density or hypersialylation in tumors has been described. Recent studies have identified mechanisms for immune evasion based on sialoglycan interactions with immunoregulatory Siglec receptors that are exploited by tumor cells and microorganisms alike. Siglecs are mostly inhibitory receptors similar to known immune checkpoints including PD-1 or CTLA-4 that are successfully targeted with blocking antibodies for cancer immunotherapy. Here, we summarize the known changes of sialic acids in cancer and the role Siglec receptors play in cancer immunity. We also focus on potential ways to target these Siglec receptors or sialoglycans in order to improve anti-cancer immunity

Research Techniques Made Simple: Profiling Cellular Energy Metabolism

The analysis of cellular metabolism is attracting increasing interest. Glycolysis and oxidative phosphorylation are intertwined with one another and dozens of other pathways to ultimately produce energy and maintain cellular fitness. However, cellular metabolism is much more than this. Metabolism underlies the proliferation, differentiation, and function of cells as well as the coordination of intercellular communication. Investigating metabolism allows the interpretation of cellular behavior in health and disease. In this article, we aim to demystify the complexity of cellular metabolism and explain the common approaches to study it. Whereas the analysis of cellular metabolism by western blot or flow cytometry might be accessible to most investigators, the functional and comprehensive analyses obtained with a Seahorse Analyzer or mass spectrometer come with monetary and logistical hurdles. We believe that the application of these techniques, together with collaborative efforts between scientists and clinicians, will uncover disease mechanisms and open novel therapeutic avenues for unmet clinical needs in the field of dermatology

Targeted Desialylation Overcomes Glyco-Immune Checkpoints and Potentiates the Anticancer Immune Response in Vivo

Currently approved immune checkpoint inhibitor (ICI) therapies targeting the PD-1 and CTLA-4 receptor pathways are powerful treatment options for certain cancers; however, the majority of patients across cancer types still fail to respond. Addressing alternative pathways that mediate immune suppression could enhance ICI efficacy. One such mechanism is the increase in sialic acid-containing proteins and lipids (sialoglycans) in malignancy, which recently has been shown to inhibit immune cell activation through multiple mechanisms including Siglec receptor binding, and therefore represents a targetable glyco-immune checkpoint. Here, we report the design of a trastuzumab- sialidase conjugate that potently and selectively strips diverse sialoglycans from breast cancer cells in vivo. In a syngeneic orthotopic HER2+ breast cancer model, targeted desialylation delayed tumor growth and enhanced immune cell infiltration and activation, leading to prolonged survival of mice with trastuzumab-resistant breast cancer. Thus, antibody-sialidase conjugates represent a promising modality for cancer immune therapy.</div

Integral field spectroscopy of radio galaxy B2 0902+34

We have used the Visible Integral-field Replicable Unit Spectrograph Prototype (VIRUS-P), a new Integral Field Unit (IFU) Spectrograph, to study the spatially and spectrally resolved Lyman-[Greek small letter alpha] emission line structure in the radio galaxy B2 0902+34 at z [similar to] 3.4. VIRUS-P has a large field of view (3.2 sq. arcmin) and is very sensitive to low surface brightness emission. A halo of Ly [Greek small letter alpha] emission with velocity dispersion of [similar to] 600km s⁻¹ extends to 100 kpc, larger than previously detected with narrowband imaging and longslit spectroscopy. A newly discovered blue emission feature appears in the southwest with a velocity separation of [similar to] −700 km s⁻¹. We interpret this emission feature as the far side ionization cone with central infall while the brighter, more circularly distributed, and distinct kinematic component is the near side ionization cone. We present a simple model which reproduces the optical spectroscopic and radio data. We have also made the first optical detection of the neutral hydrogen (HI) absorption feature presented in earlier radio data. Lastly, we have searched the surrounding 3.2 sq. arcmin for companion galaxies. To a flux level of [similar to] 7×10⁻¹⁷ erg s⁻¹ cm⁻², we detect one possible companion in Lyman-[Greek small letter alpha]. We interpret the system as a proto-giant elliptical galaxy in a protocluster still in the act of mass accumulation.Astronom

Plasmacytoid dendritic cell activation is dependent on coordinated expression of distinct amino acid transporters

Human plasmacytoid dendritic cells (pDCs) are interleukin-3 (IL-3)-dependent cells implicated in autoimmunity, but the role of IL-3 in pDC biology is poorly understood. We found that IL-3-induced Janus kinase 2 dependent expression of SLC7A5 and SLC3A2, which comprise the large neutral amino acid transporter, was required for mammalian target of rapamycin complex 1 (mTORC1) nutrient sensor activation in response to toll-like receptor agonists. mTORC1 facilitated increased anabolic activity resulting in type I interferon, tumor necrosis factor, and chemokine production and the expression of the cystine transporter SLC7A11. Loss of function of these amino acid transporters synergistically blocked cytokine production by pDCs. Comparison of in vitro-activated pDCs with those from lupus nephritis lesions identified not only SLC7A5, SLC3A2, and SLC7A11 but also ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2) as components of a shared transcriptional signature, and ENPP2 inhibition also blocked cytokine production. Our data identify additional therapeutic targets for autoimmune diseases in which pDCs are implicated