bims-trytim 2024-06-09 papers

Issue of 2024–06–09
five papers selected by
Jialin Feng, University of Dundee

Crit Rev Oncol Hematol. 2024 Jun 02. pii: S1040-8428(24)00150-1. [Epub ahead of print] 104407

Comprehensive Approach to Cancer Immunotherapy - Simultaneous Targeting of Myeloid-derived Suppressor Cells and Cancer Cells with AFP Conjugates.

Vladimir N Pak, Igor A Sherman.

The immune system plays a pivotal role in combating diseases, including cancer, with monocytes emerging as key regulators of immune response dynamics. This article describes a novel strategy for cancer treatment centered on depleting myeloid-derived suppressor cells (MDSCs), to enhance the overall immune response while simultaneously targeting cancer cells directly. Alpha-fetoprotein (AFP) is an oncofetal protein that plays an important role in delivering nutrients to immature monocytes, embryonic, and cancer cells in a targeted manner. AFP can be repurposed, making it a vehicle for delivering toxins, rather than nutrients to kill cancer cells and deplete MDSCs in the tumor microenvironment (TME). Depleting monocytes not only stimulates the immune system but also improves the lymphocyte-to-monocyte ratio (LMR), often low in cancer patients. AFP combined with cytotoxic drugs, offers dual benefit-immune stimulation and targeted chemotherapy. Studies in xenograft models demonstrated high efficacy and safety of AFP-toxin conjugates, surpassing conventional targeted chemotherapy. Such conjugates have also been reported to provide superior efficacy and safety in cancer patients compared to chemotherapy. This approach, using AFP conjugated with toxins, either covalently or non-covalently, presents a safe and highly effective option for cancer immuno/chemotherapy.

Keywords: AFP/AFP receptors; LMR; MDSCs; TME; immunotherapy; targeted chemotherapy

DOI: https://doi.org/10.1016/j.critrevonc.2024.104407

Placenta. 2024 May 23. pii: S0143-4004(24)00255-8. [Epub ahead of print]154 9-17

The role of aryl hydrocarbon receptors in nutrient metabolism and immune regulation at the maternal-fetal interface.

Yuchen Li, Xiaojun Yu, Jing Shi, Jie Zhao, Lei Li.

The maternal-fetal interface is composed of the placenta, which is affiliated with the fetus, and the maternal decidua. During pregnancy, the placenta is mainly responsible for nutrient transport and immune tolerance maintenance, which plays a key role in fetal growth and development and pregnancy maintenance. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that exists in various cell types at the maternal-fetal interface and is involved in multiple cellular processes. Recent studies have highlighted the role of AhR in regulating various physiological processes, including glucose and lipid metabolism, as well as tryptophan metabolism and immune responses, within non-pregnant tissues. This review shifts focus towards understanding how AhR modulation impacts metabolism and immune regulation at the maternal-fetal interface. This may implicate the development of pregnancy-related complications and the potential target of the AhR pathway for therapeutic strategies against poor pregnancy outcomes.

Keywords: Aryl hydrocarbon receptor; Immune tolerance; Maternal–fetal interface; Metabolism; Placenta; Trophoblast

DOI: https://doi.org/10.1016/j.placenta.2024.05.134

Mod Pathol. 2024 Jun 05. pii: S0893-3952(24)00112-1. [Epub ahead of print] 100532

Expression and Prognostic Significance of LAG-3, TIGIT, VISTA, and IDO1 in Endometrial Serous Carcinoma.

Hao Chen, Kyle Molberg, Kelley Carrick, Shuang Niu, Glorimar Rivera Colon, Katja Gwin, Cheryl Lewis, Jayanthi Lea, Vandana Panwar, Wenxin Zheng, Diego H Castrillon, Elena Lucas.

Endometrial serous carcinoma (ESC) is an uncommon, aggressive type of endometrial cancer. While immune checkpoint blockade has emerged as a promising treatment option for endometrial carcinomas, research on the expression of immune checkpoints that could serve as prospective immunotherapy targets in ESC is limited. We examined the prevalence and prognostic value of LAG-3, TIGIT, VISTA, and IDO1 in 94 cases of ESC and correlated their expression with CD8+ and FOXP3+ tumor infiltrating lymphocytes (TIL). We observed a positive correlation between LAG-3, TIGIT and VISTA expressed on immune cells, and between these markers and CD8+ and FOXP3+ TIL density. In Kaplan-Meier survival analysis, tumors with high levels of LAG-3 and TIGIT expression had better progression free survival (PFS) and overall survival (OS) than those with lower levels of expression (LAG-3: PFS, p=0.03, OS, p=0.04; TIGIT: PFS, p=0.01, OS, p=0.009). In multivariate analysis, only high TIGIT expression was of independent prognostic value for better overall survival. VISTA expression in immune or tumor cells, and IDO1 expression in tumor cells, did not show a significant association with survival. Our data indicate that LAG-3, TIGIT, and VISTA immune checkpoints have roles in the microenvironment of ESC, and their expression patterns highlight the complex interactions among the different components of this system. High levels of these markers, together with high CD8+ TIL, suggests the potential immunogenicity of a subset of these tumors. Further studies are needed to elucidate the roles of various immune components in the ESC microenvironment and their association with intrinsic tumor properties.

DOI: https://doi.org/10.1016/j.modpat.2024.100532

J Hematol Oncol. 2024 Jun 06. 17(1): 41

Ferroptosis: principles and significance in health and disease.

Fangquan Chen, Rui Kang, Daolin Tang, Jiao Liu.

Ferroptosis, an iron-dependent form of cell death characterized by uncontrolled lipid peroxidation, is governed by molecular networks involving diverse molecules and organelles. Since its recognition as a non-apoptotic cell death pathway in 2012, ferroptosis has emerged as a crucial mechanism in numerous physiological and pathological contexts, leading to significant therapeutic advancements across a wide range of diseases. This review summarizes the fundamental molecular mechanisms and regulatory pathways underlying ferroptosis, including both GPX4-dependent and -independent antioxidant mechanisms. Additionally, we examine the involvement of ferroptosis in various pathological conditions, including cancer, neurodegenerative diseases, sepsis, ischemia-reperfusion injury, autoimmune disorders, and metabolic disorders. Specifically, we explore the role of ferroptosis in response to chemotherapy, radiotherapy, immunotherapy, nanotherapy, and targeted therapy. Furthermore, we discuss pharmacological strategies for modulating ferroptosis and potential biomarkers for monitoring this process. Lastly, we elucidate the interplay between ferroptosis and other forms of regulated cell death. Such insights hold promise for advancing our understanding of ferroptosis in the context of human health and disease.

Keywords: Biomarker; Cancer therapy; Ferroptosis; Human disease; Immunity

DOI: https://doi.org/10.1186/s13045-024-01564-3

Brain Res Bull. 2024 May 30. pii: S0361-9230(24)00124-2. [Epub ahead of print] 110991

The Molecular Mechanism of ferroptosis and Its Relationship with Parkinson's Disease.

Yan Su, Yue Jiao, Sheng Cai, Yang Xu, Qi Wang, Xianwen Chen.

Neurodegenerative diseases such as Parkinson's disease (PD) have complex pathogenetic mechanisms. Genetic, age, and environmental factors are all related to PD. Due to the unclear pathogenesis of PD and the lack of effective cure methods, it is urgent to find new targets for treating PD patients. Ferroptosis is a form of cell death that is reliant on iron and exhibits distinct morphological and mechanistic characteristics compared to other types of cell death. It encompasses a range of biological processes, including iron/lipid metabolism and oxidative stress. In recent years, research has found that ferroptosis plays a crucial role in the pathophysiological processes of neurodegenerative diseases and stroke. Therefore, ferroptosis is also closely related to PD, This article reviews the core mechanisms of ferroptosis and elucidates the correlation between PD and ferroptosis. In addition, new compounds that have emerged in recent years to exert anti PD effects by inhibiting the ferroptosis signaling pathway were summarized. I hope to further elaborate the relationship between ferroptosis and PD through the review of this article, and provide new strategies for developing PD treatments targeting ferroptosis.

Keywords: ACSL4; GSH; LPO; Parkinson's disease; ROS; ferroptosis

DOI: https://doi.org/10.1016/j.brainresbull.2024.110991