Immuno-Oncology 360° Community News’ Post

It is out! A new study, led by Linnea Kristenson from my group demonstrates that loss of function mutations in TMEM30 enable escape from NK cell cytotoxicity. We used NK cells in a genome-wide CRISPR screen of K562 cells at a moderate selection pressure to identify structures implicated in NK cell cytotoxicity. Among the top-enriched genes we found TMEM30A to be important for NK cell killing of leukemic cells. TMEM30a encodes a subunit of a flippase that transports phospholipids in the plasma membrane, and TMEM30a-deficent cells displayed elevated levels of extracellular PtdSer. TMEM30a-KO K562 cells were more resistant to NK cell cytotoxicity, but killing could be restored by blocking PtdSer with Annexin V or by blocking its receptor TIM-3. The NK-resistant phenotype of TMEM30a-deficient cells was not specific for K562 cells. Several leukemia and lymphoma cell lines displayed elevated PtdSer levels and reduced sensitivity to NK cells after deletion of the TMEM30A gene. TMEM30A mutations are recurrently found in lymphoma, and our study suggests that this may be an NK cell-evasive strategy in these malignancies. Thanks to co-authors Chiara Badami, Erna Islamagić, Brwa Ali Hussein, Angelica Ljungberg, Silvia Pesce and others not using Linkedin. Read the full story in PNAS - https://lnkd.in/dfNNC7Bh

Did you know that a significant portion of our genetic code, once dismissed as “junk DNA,” might hold a key to understanding diseases like autoimmune conditions, cancer, and aging?   Scientists have uncovered a fascinating aspect of our genome, revealing how a puzzling virus-like element known as LINE-1 that was previously ignored or deemed unimportant could in fact be a game-changer in our understanding of health and disease.   LINE-1 may also explain an important mystery: population studies of HIV patients whose disease is controlled by drugs called reverse transcriptase inhibitors have shown that these patients have about half the risk of other people of developing common cancers like breast, colon, and prostate cancer. These drugs also inhibit LINE-1. Could LINE-1 activity be a major contributor to cancer risk?   A new, groundbreaking study led by researchers at Massachusetts General Hospital, to be published in Nature, has unveiled the 3D structure of a key component of LINE-1, a protein called the reverse transcriptase enzyme ORF2p. The study also shows how it ORF2p works and how certain HIV drugs inhibit it.   Scientist Martin Taylor, MD, PhD, and colleagues have explored LINE-1 function and made a stunning discovery – ORF2p can make DNA in the cytoplasm of cells, and this leads to inflammation through specific innate immune ‘virus’ sensors. This may be an underlying cause of autoimmune diseases, like lupus, acting as a nidus for inflammation. It may explain inflammation in our tissues in a state called ‘senescence’ that is thought to contribute to aging.   LINE-1 can also damage the genome, and inhibitors can block both the inflammatory and DNA-damaging aspects.   Understanding this process provides a potential pathway to develop new therapies for autoimmune diseases, cancer, neurodegeneration, and even aging-related issues, which translates to exciting possibilities for novel treatments and therapies that could change the landscape of medicine as we know it. Read more: https://lnkd.in/g37hhifi

Tumor is a complex ecosystem of highly heterogeneous cancer cells and various immune cells in their microenvironment (#TME). The prognosis and responses to treatment are often dependent on genetic profiles on both cancer and immune cells. Thus the rise of #immunogenomics, in recent years in clinics, as nicely reported in this recent Inside Precision Medicine article. New tools can bring valuable insights to the intriguing interplay of immune system and genetics in cancer -- as well as in other diseases. Singleron offers an array of products that deciphers both transcriptome and immune receptor repertoire profiles at single cell or bulk level to address different scientific/clinical questions, sample throughput, and budgets (For example, #GEXSCOPE Single Cell VDJ Library Kit; #sCircle Single Cell Full Length VDJ Kit; and AccuraCode High Throughput RNA+TCR+BCR kits). Contact us if you would like to find out more: info@singleron.bio

I'm excited to share our preprint in review on a B cell specific method for HIV therapy by editing hematopoietic stem and progenitor cells! We use targeted gene insertion at the CCR5 locus in HSPCs to allow sustained delivery of broadly neutralizing anti-HIV antibodies through lineage-specific expression. We show high efficiency locus specific knock-in in human HSPCs which remain functional for development of all hematopoietic lineages in vivo after editing. We also demonstrate efficient knock-in in primary human B cells derived from peripheral blood of healthy donors, which allows expression of neutralizing concentrations of multiple broadly neutralizing antibodies currently in development. Check it out! https://lnkd.in/gXtiGnvJ

Genetically modified T cell immunotherapies have shown impressive results in treating B cell acute lymphoblastic leukemia by using a patient's own T cells to attack cancer. These methods also hold promise for treating a wide range of other conditions, including various cancers, infectious diseases, and autoimmune disorders. This is achieved by inserting a transgenic T cell receptor or a chimeric antigen receptor into T cells, allowing them to specifically target and destroy cancer cells. However, early research indicates a need for the development of more sophisticated genetic controls over these engineered T cells to maximize their safety and effectiveness. In this review, authors discuss how advancements in genetics and genome engineering are paving the way for the next wave of adoptive T cell therapies. https://lnkd.in/e2-YAZsM

Part 3 of the four-part series about cell therapy from Fierce Biotech. Definitely worth a full read and provided the link and a summary of part 3 below. 𝐏𝐚𝐫𝐭 3: 𝐂𝐞𝐥𝐥 𝐭𝐡𝐞𝐫𝐚𝐩𝐲 𝐫𝐞𝐜𝐤𝐨𝐧𝐢𝐧𝐠: 𝐏𝐢𝐯𝐨𝐭 𝐭𝐨 𝐚𝐮𝐭𝐨𝐢𝐦𝐦𝐮𝐧𝐞 𝐥𝐞𝐚𝐯𝐞𝐬 𝐮𝐧𝐦𝐞𝐭 𝐧𝐞𝐞𝐝 𝐢𝐧 𝐨𝐧𝐜𝐨𝐥𝐨𝐠𝐲 𝐀𝐫𝐭𝐢𝐜𝐥𝐞 𝐥𝐢𝐧𝐤: https://lnkd.in/gAWRXse7 𝐏𝐢𝐨𝐧𝐞𝐞𝐫𝐢𝐧𝐠 𝐂𝐚𝐬𝐞 𝐒𝐭𝐮𝐝𝐲 -A 20-year-old patient with severe lupus received experimental CD19 CAR-T cell therapy at University Hospital Erlangen in Germany. -Resulted in remarkable recovery and long-term remission. 𝐂𝐥𝐢𝐧𝐢𝐜𝐚𝐥 𝐒𝐮𝐜𝐜𝐞𝐬𝐬 -Out of 15 patients treated for lupus, systemic sclerosis, and idiopathic inflammatory myositis, nearly all remained disease-free and off treatment. 𝐈𝐧𝐝𝐮𝐬𝐭𝐫𝐲 𝐈𝐧𝐭𝐞𝐫𝐞𝐬𝐭 -Positive outcomes have drawn significant attention from companies like CRISPR Tx, Kyverna, Novartis, and Regeneron. 𝐏𝐫𝐨𝐦𝐢𝐬𝐢𝐧𝐠 𝐃𝐚𝐭𝐚 -Early results indicate that CAR-T therapy can induce durable, drug-free remission in severe autoimmune diseases. 𝐋𝐨𝐠𝐢𝐜𝐚𝐥 𝐓𝐫𝐚𝐧𝐬𝐢𝐭𝐢𝐨𝐧 -Overlap in targeting B cells between oncology and autoimmune diseases supports the rational switch from cancer treatment to autoimmune therapy. 𝐂𝐮𝐫𝐫𝐞𝐧𝐭 𝐓𝐫𝐢𝐚𝐥𝐬 -Companies like Cartesian Therapeutics are conducting trials on CAR-T therapies for autoimmune conditions such as myasthenia gravis. 𝐑𝐞𝐚𝐬𝐬𝐮𝐫𝐢𝐧𝐠 𝐏𝐫𝐨𝐭𝐨𝐜𝐨𝐥𝐬 -University Hospital Erlangen’s research shows that the same CAR-T protocols used for cancer can be applied to autoimmune diseases with limited side effects. 𝐂𝐨𝐧𝐬𝐢𝐝𝐞𝐫𝐚𝐭𝐢𝐨𝐧𝐬 𝐟𝐨𝐫 𝐒𝐮𝐜𝐜𝐞𝐬𝐬 -Future effectiveness will depend on disease and patient selection, target selection, and managing relapses. 𝐄𝐱𝐩𝐚𝐧𝐝𝐢𝐧𝐠 𝐀𝐩𝐩𝐥𝐢𝐜𝐚𝐭𝐢𝐨𝐧𝐬 -Researchers are exploring CAR-T therapy for other conditions, including HIV, cardiac fibrosis, hepatitis B, and cell senescence.

Great to see this article reviewing the most recent screening and treatment guidelines for men with BRCA mutations. Even though women's breast and ovarian cancers are most frequently associated with BRCA mutations, men also face risks of cancer due to these genes, and there is much less public awareness of the risk to men. According to Heather Cheng, MD, PhD, the director of the Fred Hutch Prostate Cancer Genetics Clinic, "Not enough men are getting genetic testing to see if they carry a BRCA1 or BRCA2 gene variant that increases their cancer risk. . . . And the men who know they are carriers get tested for their daughters, but don't always know why it's important for their own health." It's a subject close to my heart, as my own grandfather died of a very aggressive prostate cancer--undoubtedly due to the same BRCA1 mutation I inherited. The mutation has been evident in five generations of my family, with more males currently living with our family mutation than females. Although two of my own sons inherited my BRCA1 mutation, that knowledge is allowing them to be proactive in their health care. Knowledge gained from genetic testing, together with appropriate medical surveillance, saves lives! Dr. Cheng is the lead author of BRCA1, BRCA2, and Associated Cancer Risks and Management for Male Patients, JAMA Oncology (2024). DOI: 10.1001/jamaoncol.2024.2185 My Faulty Gene #brca #malecancer #knowyourrisk #cancerrisk #genetictesting #prostatecancer #pancreaticcancer #malebreastcancer #breastcancer #ovariancancer #melanoma

Exciting breakthrough in T cell therapies! 🧬🧫🔬This article explores leveraging naturally occurring mutations, specifically the gene fusion CARD11–PIK3R3 found in CD4+ cutaneous T cell lymphoma. This mutation enhances T cell signaling and anti-tumor efficacy, offering hope for improved T cell therapies #celltherapy #oncology #cartcelltherapy

Natural killer cell therapies. https://lnkd.in/eGkRji97 "Natural killer (NK) cells are lymphocytes of the innate immune system. A key feature of NK cells is their ability to recognize a wide range of cells in distress, particularly tumour cells and cells infected with viruses. They combine both direct effector functions against their cellular targets and participate in the generation, shaping and maintenance of a multicellular immune response. As our understanding has deepened, several therapeutic strategies focused on NK cells have been conceived and are currently in various stages of development, from preclinical investigations to clinical trials. Here we explore in detail the complexity of NK cell biology in humans and highlight the role of these cells in cancer immunity. We also analyse the harnessing of NK cell immunity through immune checkpoint inhibitors, NK cell engagers, and infusions of preactivated or genetically modified, autologous or allogeneic NK cell products." New review on Natural Killer cell therapies, by Eric Vivier and larger team

🔬 A breakthrough in blood cancer research! A joint study by the University of Helsinki and Dana-Farber Cancer Institute, Harvard Medical School, reveals how blood cancer cells outsmart the immune system’s NK cells. 🧬 Using cutting-edge techniques like single-cell RNA sequencing and CRISPR-Cas9 gene editing, the team identified key mechanisms behind cancer cells' resistance to immune attacks. 👩🔬 This discovery, led by experts Olli Dufva, Sara Gandolfi, MD, PhD, Satu Mustjoki, and Constantine Mitsiades, could revolutionize cancer immunotherapies, offering hope for more effective treatments with fewer side effects. 🌟 Supported by prominent foundations, this research paves the way for personalized cancer treatments and a deeper understanding of immune-cancer interactions. #CancerResearch #Immunotherapy #BloodCancer #NKCells #InnovationInScience #UniversityOfHelsinki #DanaFarber #HarvardMedicalSchool #HealthcareEvolution #ResearchImpact