Alvaro Lladser’s Post

My Honours student, Jane (Jiabao) Tian, has recently published a review article in IJMS as part of the Special Issue Molecular Research and New Therapy in Melanoma and Other Skin Cancers. This paper provided an overview of major immune checkpoint inhibitor therapies and discussed the essential immune characteristics linked to how patients respond to or resist therapy. The paper also outlined the fundamental biological elements, such as cellular makeup and communication networks within tumors, to deepen our comprehension of how immunotherapy interacts with melanoma. This exploration offers valuable insights for future research, aiding in the identification of drug targets and predictive biomarkers. Link: https://lnkd.in/gJBDMzgA #melanoma #immunotherapy #singlecell #sequencing #spatial #tumourmicroenvironment MDPI

Our new paper entitled " The nexus of natural killer cells and melanoma tumor microenvironment: crosstalk, chemotherapeutic potential, and innovative NK cell-based therapeutic strategies" is now published in the Cancer Cell International . Journal: https://lnkd.in/d68R6fBX    The metastasis of melanoma cells to regional lymph nodes and distant sites is an important contributor to cancer-related morbidity and mortality among patients with melanoma. This intricate process entails dynamic interactions involving tumor cells, cellular constituents, and non-cellular elements within the microenvironment. Moreover, both microenvironmental and systemic factors regulate the metastatic progression. Central to immunosurveillance for tumor cells are natural killer (NK) cells, prominent effectors of the innate immune system with potent antitumor and antimetastatic capabilities. Recognizing their pivotal role, contemporary immunotherapeutic strategies are actively integrating NK cells to combat metastatic tumors. Thus, a meticulous exploration of the interplay between metastatic melanoma and NK cells along the metastatic cascade is important. Given the critical involvement of NK cells within the melanoma tumor microenvironment, this comprehensive review illuminates the intricate relationship between components of the melanoma tumor microenvironment and NK cells, delineating their multifaceted roles. By shedding light on these critical aspects, this review advocates for a deeper understanding of NK cell dynamics within the melanoma context, driving forward transformative strategies to combat this cancer.    #Melanoma,#  Metastasis, #Natural killer cells, #Tumor microenvironment

Exciting news in the battle against metastatic melanoma! 🎉 The FDA has approved Amtagvi (lifileucel), the first cellular therapy using adoptive cell transfer (ACT) for the treatment of adult patients with unresectable or metastatic melanoma that has advanced after previous treatments. It is an autologous ACT therapy in which the patient's own T cells that have invaded the tumour microenvironment are utilised as tumor-infiltrating lymphocytes (TILs). Amtagvi generates a potent anti-tumor response by isolating these TILs, selecting those that can precisely recognise and eliminate the patient's cancer cells, and then expanding them in order to re-infuse them back into the patient. Amtagvi highlights some key pros of the ACT approach: - Personalized medicine 💊 : Amtagvi is manufactured using the patient's own tumor-specific T cells, and is therefore highly specific to the patient's unique mutations. - Novel mechanism 🧫: By isolating, expanding, and re-engineering a patient's T cells ex vivo, Amtagvi generates a more potent anti-tumor response compared to conventional treatments. - Promising efficacy 🔬: 31.5% of patients achieved an objective response, including complete responses, which is remarkable for advanced melanoma. Amtagvi's approval is incredibly exciting - showcasing the clinical translation of cellular engineering for precision cancer treatment. This paradigm shift with personalized cellular therapies opens up endless possibilities. I'm keen to learn how we can further refine and optimize these individualized immunotherapies going forward. #FDAApproval #CellularTherapy #Melanoma #ImmunoOncology #Cancer

**Manuscript Alert: We previously demonstrated that costimulatory signals are necessary for tumor infiltrating lymphocytes (TILs) to effectively mediate tumor responses. With our Instil Bio colleagues, we now report on the evaluation of a costimulatory CAR technology called CoStAR that enables TILs to receive potent, immune-enhancing costimulatory signals upon recognition of autologous tumor cell antigens via the T cell's TCR. TILs engineered to express CoStAR exhibit improved proliferation and anti-tumor activity in vitro even in the absence of IL-2. CoStAR TILs also show enhanced T cell survival after transfer, resulting in enhanced control of tumor growth and improved host survival. https://lnkd.in/ePjRgFZE

New Insights into Melanoma Brain Metastases 🧠 Melanoma brain metastases (MBM) are a serious complication of melanoma, with a poor prognosis. Researchers have conducted a multi-omic analysis of a large cohort of melanoma patients to gain a better understanding of the biology of MBM and identify potential therapeutic targets. Key findings: -MBM exhibit lower interferon-gamma (IFNγ) scores and T cell-inflamed scores compared to primary cutaneous melanoma (PCM) or extracranial metastases (ECM). -MBM have fewer computationally inferred immune cell infiltrates, which correlated with lower TNF and IL12B mRNA levels. -Ingenuity pathway analysis (IPA) revealed suppression of inflammatory responses and dendritic cell maturation pathways in MBM. -MBM demonstrate a higher frequency of pathogenic PTEN mutations and angiogenic signaling. -Oxidative phosphorylation (OXPHOS) is enriched in MBM and negatively correlated with NK cell and B cell-associated transcriptomic signatures. These findings suggest that MBM have a unique tumor microenvironment that is less favorable for immune responses. Modulating metabolic or angiogenic pathways in MBM may improve responses to immunotherapy in this difficult-to-treat patient subset. #PrecisionMedicine #CancerTreatment #Melanoma #BrainMetastases #CancerResearch🧬💉

CD8+ T cells are capable of killing MHC-I-deficient tumor cells. This effect appears to be dependent on natural killer group 2D (NKG2D) and NKG2D ligands (NKG2DLs) expressed on T cells and tumor cells respectively. NKG2DLs are highly expressed in MHC-I-deficient tumors. https://lnkd.in/edhbE86k

🔥 Hot off the press! 🔥 Check out a new pre-print available at bioRxiv lead by Evelyn Lattmann and Mitch Levesque at Universitätsspital Zürich, titled ”Label-Free Melanoma Phenotype Classification Using Artificial Intelligence-Based Morphological Profiling”. Using the REM-I system, the group categorized patient-derived melanoma cells into melanocytic and mesenchymal phenotypes. Deepcell REM-I’s AI-enabled label-free method successfully predicted phenotypic shifts, as validated by scRNA-Seq. The study demonstrates a significant link between cell morphology and melanoma cell state, paving the way for AI-informed guidance in oncology applications. The data shows “significant potential for a variety of applications, advancing both biological and clinical research in melanoma”. #REMi #Morpholomics #Melanoma #Oncology #SkinCancer #HealthcareInnovation https://lnkd.in/gyYvBCXF

Breast cancer-on-chip for patient-specific efficacy and safety testing of CAR-T cells Physiologically relevant human models that recapitulate the challenges of solid tumors and the tumor microenvironment (TME) are highly desired in the chimeric antigen receptor (CAR)-T cell field. A breast cancer-on-chip model with an integrated endothelial barrier that enables the transmigration of perfused immune cells, their infiltration into the tumor, and concomitant monitoring of cytokine release during perfused culture over a period of up to 8 days was developed. Here, its use for investigating CAR-T cell efficacy and the ability to control the immune reaction with a pharmacological on/off switch was exemplified. Additionally, the primary breast cancer organoids was integrated to study patient-specific CAR-T cell efficacy. The modular architecture of the developed tumor-on-chip paves the way for studying the role of other cell types in the TME and thus provides the potential for broad application in bench-to-bedside translation as well as acceleration of the preclinical development of CAR-T cell products. https://lnkd.in/gxXzkkmH

Insight: Age-related changes in the skin could contribute to higher rates of melanoma metastases in older individuals. Insights: - In 2024, an estimated 200,000 people in the US will be diagnosed with melanoma. - Increased stiffness in aging skin leads to elevated ICAM1 levels, promoting melanoma growth. - Treating melanoma with drugs that block ICAM1 reduces tumor size and metastasis. Researchers from Johns Hopkins Kimmel Cancer Center found that targeting ICAM1 with drugs can potentially revolutionize melanoma treatment for older patients. The study's focus on age-related skin changes shedding light on melanoma metastasis has broader implications for cancer treatment and understanding age-related diseases. Question: How can advancements in targeting ICAM1 in melanoma treatment pave the way for more effective therapies in age-related cancers? #CancerResearch #HealthScience #AgingResearch https://lnkd.in/e-sWKfFu

Our understanding of cancer metastasis is linked to our ability to characterize cell phenotypes and cycles. An exciting preprint from our partners at Universitätsspital Zürich demonstrates a way to accurately and reliably phenotype melanoma cells transitioning from melanocytic to mesenchymal states using #deepcell #REM-I. This label-free, morphology-based approach marks significant progress. As the paper states, "Definitive and rigorous classification of these phenotypic states has been challenging with conventional biomarker-based methods, and high-parameter molecular methods are cell-destructive, labor-intensive, and time-consuming."