Written By: Rebecca Tweedell
Written By: Kaitlyn Sadtler
Original Article: Stanczak et al. JCI 2018
The Gist of It:
How does your body tell its own cells from bacterial cells? What’s more – how does it tell cancerous cells from healthy cells? It’s a tricky problem because cancerous cells and healthy cells are both technically your cells, just one is bad. There are many ways that your body protects itself from creating immune cells that will mistake its own healthy cells for dangerous invaders and attack them. If these systems go awry, on one side you can see autoimmune diseases, such as multiple sclerosis and type-1 diabetes, and on the other side, diseases such as cancer can evade detection as dangerous by masquerading as normal cells. So, figuring out how these cancer cells are evading detection by our immune system can help us find targets for new cancer therapeutics. In a recent paper out of the University Hospital Basel in Switzerland, researchers describe a way in which cancer cells are camouflaged as normal cells. When certain kinds of immune cells – T cells — enter a tumor, things can (generally) go one of two ways: either the T cells will recognize the cancer and kill the cells, or they will turn into what we call regulatory T cells. As the name suggests, these cells regulate the immune response, dampening inflammation – which is exactly what we don’t want when it comes to cancer. We want our T cells to see the cancer and attack it. Michal Stanczak and colleagues describe molecules known as Siglecs on T cells that are responsible for recognizing patterns in the proteins of normal cells so that the T cells know not to kill those cells – because they are us, or “self”. Cancer, which is still technically us, but a damaged/altered version, can make T cells increase the amount of Siglec they produce. This means that the T cells are being told that the cancer is their own body so therefore they shouldn’t attack it. These studies present a new potential target for cancer treatment; decreasing the amount of Siglecs in T cells can decrease cancer’s ability to hide from our immune system.
The Nitty Gritty:
Stanczak et al. described a regulatory pathway by which tumor-infiltrating T cells upregulated Siglecs. These Siglecs, specifically Siglec-9, are acting as self-associated molecular pattern (SAMP) receptors which are associated with other regulatory markers such as PD-1 and TIM3. Such increases in Siglec-9 expression on tumor-infiltrating lymphocytes were noted in clinical samples from patients with non-small cell lung cancer, colorectal cancer, and ovarian cancer. By inducing Siglec-9 expression on CD4+ T cells in a murine MC38 model, researchers showed that expression of Siglec-9 on CD4+ T cells correlated with an increased tumor volume and growth rate compared to a wild type control. Furthermore, if cells were desialynated (either enzymatically or through knockout of a rate-limiting enzyme in the sialic acid biosynthesis pathway, UDP-N-acetylglucosamine-2-epimerase) CD8+ T cell-mediated cell killing was increased in vitro. This presents a putative new therapeutic target for cancer immunotherapies.
Original Research Article: Stanczak, Michal A., et al. “Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells.” The Journal of clinical investigation (2018).
Written By: Padmini Pillai
Original Article: Mihaylova et al. Cell Reports 2018
The Gist of It:
As the cold season is upon us, it’s time we think about how to protect ourselves against rhinovirus, the most frequent cause of the common cold. Rhinovirus enters the respiratory tract through the nasal passages and can spread down to larger airways of the lungs called bronchi. Epithelial cells, which line the respiratory tract, can detect rhinovirus and trigger immune responses. Although nasal and bronchial epithelial cells can be infected by rhinovirus, a study published this week demonstrates that they respond to infection in different ways.
The authors obtained human nasal and bronchial airway epithelial cells and infected them with rhinovirus. After infection, nasal epithelial cells produced significantly more interferon, a key antiviral molecule that turns on a plethora of genes to stop the virus. On the other hand, bronchial cells produced less interferon but higher amounts of a molecule called NRF2. NRF2 protects cells against damage triggered by injury and inflammation, and is often found in large amounts in the lungs of smokers.
Therefore, immune responses by cell types in different parts of the respiratory tract, from the nose down to the lungs, react to stimuli differently. This makes sense — your nasal passage encounters many pathogens and serves as the entry point for viruses into the respiratory tract, as well as your frontline defense against them, so interferon is critical for protection there. Further down in the bronchi, the consequences of inflammation and damage to the delicate lining in large airways responsible for carrying oxygen into the body is far too great, so pathways preventing damage and promoting survival to bronchial cells are of utmost importance.
Interestingly, the authors also discovered that NRF2 inhibits antiviral responses. If nasal cells were exposed to an extract of cigarette smoke and then infected with rhinovirus, they saw increased NRF2 and enhanced viral replication. So here’s the take-home message: cigarette smoking or exposure to other airway irritants such as car exhaust or environmental pollutants could inhibit your antiviral responses by turning on NRF2, making you susceptible to respiratory infections such as the common cold. Prior research from Dr. Ellen Foxman showed that lower temperatures in the nasal passage also inhibit production of interferon by nasal epithelial cells (looks like the old wives’ tale to cover your nose in the cold may be true!). So this winter, try to stay away from smokers and keep those nasal passages warm to protect yourself from the common cold!
The Nitty Gritty:
The authors cultured primary human nasal and bronchial epithelial cells. After inoculation with rhinovirus 1b or transfection with the RIG-I ligand SLR14, nasal cells produced significantly more IFNλ1 and upregulated IFNβ and ISG expression. RNA-seq and ingenuity pathway analysis revealed that stimulation with SLR14 led to a dominant interferon response in nasal cells, while bronchial cells exhibited transcripts related to the NRF2 pathway. Knockdown of NRF2 in bronchial cells resulted in increased IFN and ISG expression. Pretreatment of nasal cells with the NRF2 activator sulforaphane significantly decreased interferon and ISG transcripts after SLR14 stimulation. siRNA knockdown of NRF2 in nasal cells inoculated with rhinovirus led to enhanced ISG induction and even stronger viral restriction. Nasal epithelial cells pretreated with cigarette smoking extract and inoculated with rhinovirus had higher viral tiers, increased expression of NRF2, and decreased expression of the ISG IFIT2. This study demonstrates two different defense mechanisms in airway epithelial cells from different regions of the respiratory tract and reveals that activation of NRF2 by oxidative stress can inhibit antiviral responses.
Original Research Article: Mihaylova, Valia T., et al. “Regional Differences in Airway Epithelial Cells Reveal Tradeoff between Defense against Oxidative Stress and Defense against Rhinovirus.” Cell Reports 24.11 (2018): 3000-3007.
Written by: Ritu Raman