Year in Review: Advancements in the Fields of Life Science and Biomedicine
2024 has come to a close. In the past year, we have witnesed significant advancements in the fields of life science and biomedicine. As the year ends, we pause to honor the remarkable research that has pushed the boundaries of scientific discovery and celebrate the relentless efforts made by the scientists to pursue knowledge.
The upcoming special issues of our weekly newsletter will feature high-impact, cutting-edge articles on a broad spectrum of topics from 2024, ranging from immunotherapy for cancer to the role of gut microbiome in human health, from the origin and evolution of plants to treatments for autoimmune diseases. There will also be a special issue dedicated to the new methods, tools, diagnostics, and drugs developed by researchers. Please stay tuned to the exciting advancements and invaluable insights they bring.
Throughout the year, we have had the privilege of sharing research from scientists around the globe and we are happy to see an ever-growing community of like-minded individuals join us in the journey of exploration. With heartfelt gratitude, we invite you to continue this exploration with us as we venture into the unknown in the year ahead.
T cells play a critical role in the immune response to cancerous cells. As a result, they have long been the focus of research on immunotherapy for cancer. While offering significant promises in the fight against cancer, T cells face challenges such as potential for exhaustion and low antigen sensitivity. To address these challenges, researchers?explored various strategies. In the articles featured in this issue of the Annual Review, scientists present their findings in their attempt to optimize T?cell function and improve immunotherapeutic outcomes.
Enhancing CAR T Cell Therapies: The Role of FOXO1 in Improving Persistence and Antitumor Activity
CAR T cell therapies struggle with poor CAR T cell persistence in vivo. According to a recent study published in Nature, researchers from the University of Pennsylvania and Stanford University found that the transcription factor FOXO1 is crucial for enhancing memory and preventing exhaustion in human CAR T cells. Inhibiting or editing endogenous FOXO1 decreased memory-associated gene expression, led to an exhaustion-like phenotype, and diminished the antitumor activity of CAR T cells. CAR T cells overexpressing FOXO1 maintained their function, memory potential, and metabolic fitness under chronic stimulation, showing improved persistence and tumor control in vivo. These results highlighted that FOXO1 is clinically relevant in cancer immunotherapy.
Osr2 as a Biomechanical Checkpoint in CD8+ T Cell Exhaustion and Cancer Immunotherapy
The effects of the biomechanical property of ECM on?the functionality of tumor-reactive CD8+ T cells?remains poorly understood. In a?recent study published in Cell, researchers from China reported that the transcription factor Osr2 integrates?biomechanical signaling and promotes the terminal exhaustion of CD8+ T cells. They found that Osr2?is?induced by T cell receptor (TCR) signaling and?biomechanical stress, which is mediated by the Piezo1/calcium/CREB pathway.?It recruits HDAC3 to modify the epigenetic program, suppressing the expression of cytotoxic genes and promoting CD8+ T cell exhaustion. This study shows that targeting Osr2 could mitigate CD8+ T cell exhaustion, enhancing cancer immunotherapy efficacy. ?
Enhancing CAR T Cell Therapy with a Novel CAR Enhancer (CAR-E)
CAR T cell therapies have shown promise but face challenges in?achieving durable remissions. Extending?the?period of?efficacy requires innovative approaches. Researchers from Dana-Farber Cancer Institute and Boston University developed a CAR enhancer (CAR-E),?combining a CAR T cell antigen with an immunomodulatory molecule.?They treated multiple myeloma with?B cell maturation antigen?(BCMA)?CAR T cells, with a CAR-E comprising the BCMA fused to a low-affinity interleukin 2 (IL-2). They found that the strategy?selectively activates?IL-2 signaling in CAR T cells, promoting CAR T cell?proliferation, enhancing tumor cell clearance, and fostering the development of memory CAR T cells?while minimizing?IL-2-related?toxicities. The memory CAR T cells retain the ability to expand again when restimulated,?effectively controlling?tumor growth upon rechallenge. The CAR-E strategy?eliminates the need for complex engineering, allowing for CAR T cell therapy with lower cell doses. ?
Enhancing CAR T Cell Therapy: The Role of MEK1/2 Inhibitors in Reducing T Cell Exhaustion and Differentiation
T cell exhaustion and terminal differentiation hinder the effectiveness of CAR-T cell therapy. Researchers investigated the effects of MEK1/2 inhibitors (MEKIs) on CAR-T cells and found that MEKIs reduced CAR-T cell exhaustion and terminal differentiation, enhancing CAR-T efficacy against both hematological and solid tumors. Mechanistically, MEK inhibition decreased anabolic metabolism and suppressed the expression of c-Fos and JunB. These findings support the potential use of MEKIs to improve CAR-T therapy outcomes by targeting key molecular pathways.
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Engineering CAR Phase Separation to Enhance T Cell Immunity
CAR-T cell therapy faces challenges of?antigen sensitivity and cell persistence. A recent study in Immunity tackled these issues by introducing EB6I, an engineered?T cell receptor CD3ε?motif,?into the conventional 28Z or BBZ?CAR, promoting self-phase separation via cation-π interactions. This modification enabled the formation of mature immunological synapses,?boosting?antigen and costimulatory signaling while keeping?tonic signaling?low. EB6I CAR-T cells demonstrated enhanced cytotoxicity against low-antigen tumors and sustained efficacy.?In various murine models of primary and relapsed cancers, EB6I CAR-T cells outperformed conventional CAR-T cells in their antitumor effects against both blood and solid cancers. The findings highlight a novel strategy to enhance CAR-T cell antitumor functions through molecular engineering.
OXCT1 as an Regulator of Tumor-Associated Macrophages and Antitumor Immunity in Hepatocellular Carcinoma
Previous research revealed that ketolysis facilitates tumor progression in hepatocellular carcinoma (HCC) through OXCT1 expression,?but the role of OXCT1 in antitumor immunity remains unclear. Researchers from China and the United States jointly investigated the expression pattern of?OXCT1 in HCC?and found that suppressing OXCT1 expression in tumor-associated macrophages (TAMs) alleviated CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 pathway. OXCT1 deficiency reprogrammed TAMs toward an antitumor phenotype, leading to less?CD8+ T-cell exhaustion and elevated CD8+ T-cell?cytotoxicity. Mechanistically, increase in?OXCT1 expression in TAMs promotes?succinate accumulation, a byproduct of ketolysis, which facilitates?Arg1 transcription by raising?the H3K4me3?level?in?the Arg1 promoter.?Pharmacological inhibition of OXCT1 inhibited?Arg1 expression?and TAM polarization, slowing down?tumor growth. These findings identify OXCT1 as a key regulator of antitumor immunity in HCC.
mIDH1 Inhibition Reactivates cGAS to Boost Anti-Tumor Immunity in Liver and Brain Cancers
Isocitrate dehydrogenase 1 (IDH1) mutations are common in various cancers and produce the oncometabolite (R)-2-hydroxyglutarate (R-2HG), which disrupts enzymes involved in epigenetics and other cellular processes and contributes to T cell exclusion in solid tumors. A recent study published in Science?explored the mechanism of immune evasion associated with mIDH1. Researchers found that IDH1 mutations lead to selective hypermethylation and silencing of the cytoplasmic double-stranded DNA (dsDNA) sensor CGAS, impairing innate immune signaling. Inhibiting mIDH1 leads to DNA demethylation, restores CGAS expression and reactivates transposable element (TE) subclasses. The dsDNA generated by TE-reverse transcriptase (TE-RT) activates cGAS, initiating a viral mimicry response and enhancing antitumor immunity. This study shows that mIDH1 suppresses innate immunity epigenetically, and its inhibition can restore immune function, offering a potential therapeutic approach.
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