Andrew
Gabagat
IntereSTING Mechanism of T Cell Death
Abstract profile. Full document pending author claim.
Authors:
Andrew Gabagat, Nicholas Garaffo, Nir Hacohen
Date Created:
2025-01-01
Course Title:
Professor:
Not specified
About Paper:
Harnessing the immune system to target tumors is an increasingly activity. To understand how STING affects T cell activation, promising therapeutic approach. Stimulation of the cGAS-STING we concurrently stimulated primary human T cells with anti- pathway is a potent adjuvant therapy to increase innate and CD3/28 in the presence of STING agonists and quantified changes adaptive anti-tumor response. Activation of STING through small in surface marker expression. Interestingly, we were able to molecule agonists induces multiple antiviral signaling programs decouple STING’s channel function as the cause of cell death. including Type I interferon (IFN) production, NLRP3 mediated Our preliminary findings indicate how blocking the channel inflammation, and autophagy. Induction of STING can boost function rescues proliferation defects and decreases the production anti-tumor responses of lymphocytes through canonical IFN of reactive oxygen species. Future work includes narrowing dependent mechanisms, but recent reports suggest prolonged down up-regulated apoptotic pathways through transcriptomics STING activation causes T cell death independent of the IFN and validating in modified murine models. In the context of cancer pathway. We hypothesize that induction of STING leads to immunotherapy, better biological understanding of this pathway impaired proliferation and health in T cells due to activating informs how small molecule therapy can be utilized to promote its lesser known proton channel function. Here, we investigate tumor killing while still maintaining a patient’s adaptive immune how different branches of STING affect T cell health and population. InvestigatingHowCommensalGutBacteriaandTheirProductsPromoteAnti- Tumor Immunity Ashley Killian, Shumeng Hao, Francesca Gazzaniga University of California Berkeley | Molecular and Cellular Biology | 2027 Why some cancer patients respond to immunotherapy while isolates, E. ramosum consistently induced the highest T cell others do not remains a major clinical challenge. Emerging proliferation and cytotoxic cytokine production. Furthermore, evidence points to the gut microbiome as a critical factor, yet theRNA sequencing analysis also confirmed upregulation of IL-2, underlying mechanisms are not fully understood. We identified IFN-γ, and other cytotoxicity-related genes in E. ramosum-treated a commensal bacterium, Erysipelatoclostridium ramosum, that T cells. Mechanistically, this effect was blocked by an NF-κB overcomes microbiome-dependent resistance to immunotherapy in inhibitor, but not by inhibitors of JNK, ERK, p38, PI3K, or AKT, mice. Analysis of tumor-infiltrating immune cells revealed that E. indicating NF-κB-dependent signaling. These results suggest that ramosum colonization significantly increased proliferating CD8+ E. ramosum potently stimulates CD8+ T cell proliferation and T cells, as measured by Ki67 staining. To assess direct effects, cytotoxic activity, with evidence pointing to upregulation of NF- we treated isolated CD8+ T cells with E. ramosum pellets or κB signaling. In the future, E. ramosum may serve as a promising supernatants; only the pellets enhanced CD8+ T cell proliferation microbial approach to enhance anti-tumor immunity and improve and cytotoxicity in vitro. In a screen of 22 human gut bacterial immunotherapy outcomes. 6 Harvard-Amgen Scholars Program AnAlzheimer'sDiseaseRiskVariant ofTREM2ConfersSex-SpecificChanges in Adult Hippocampal Neurogenesis Sophia Kouznetsov, Ryan W. Castro, Se Hoon Choi Worcester Polytechnic Institute | Neuroscience | 2026 Alzheimer’s disease (AD) is a progressive neurodegenerative differentiation, and survival of NPCs, in 4-month-old male and disorder, affecting over 55 million people globally. The female mice (N = 5 per group) harboring wild-type TREM2, hippocampus, a central structure in learning and memory, is full TREM2 gene knockout, or the TREM2-R47H mutation, severely affected in AD, where impaired adult hippocampal which is the most prevalent and widely studied TREM2-mutation neurogenesis (AHN) contributes to the marked cognitive decline. that confers increased AD risk. While no genotype-specific AHN occurs in the dentate gyrus, where neural stem cells can effects were observed in proliferation or differentiation, female self-renew or differentiate into neural progenitor cells (NPCs), R47H mice exhibited increased NPC survival, suggesting a sex- eventually giving rise to mature granule neurons or glia. This specific vulnerability. Premature differentiation and subsequent process declines with age and is further disrupted in AD due depletion of the stem cell reserve are common hallmarks of to mechanisms that are yet to be fully understood. Variants AD, and the higher prevalence of AD in females is well in the immune-modulatory gene TREM2 — Triggering Receptor described. Thus, the current findings highlight a possible link Expressed on Myeloid Cells 2 — which is expressed primarily between microglial dysfunction driven by TREM2 mutations and by microglia in the central nervous system, confer up to a four- impaired neurogenesis in AD. Targeting TREM2 may offer a dual fold risk of developing AD. Due to the emerging role of microgliatherapeutic approach, modulating inflammation and supporting as regulators of AHN, understanding the role of this microglia- neurogenesis, improving cognitive outcomes beyond current specific AD risk factor in AHN regulation is imperative. Thus, plaque-targeting strategies. we quantified facets of neurogenesis, namely the proliferation,
Abstract:
Harnessing the immune system to target tumors is an increasingly activity. To understand how STING affects T cell activation, promising therapeutic approach. Stimulation of the cGAS-STING we concurrently stimulated primary human T cells with anti- pathway is a potent adjuvant therapy to increase innate and CD3/28 in the presence of STING agonists and quantified changes adaptive anti-tumor response. Activation of STING through small in surface marker expression. Interestingly, we were able to molecule agonists induces multiple antiviral signaling programs decouple STING’s channel function as the cause of cell death. including Type I interferon (IFN) production, NLRP3 mediated Our preliminary findings indicate how blocking the channel inflammation, and autophagy. Induction of STING can boost function rescues proliferation defects and decreases the production anti-tumor responses of lymphocytes through canonical IFN of reactive oxygen species. Future work includes narrowing dependent mechanisms, but recent reports suggest prolonged down up-regulated apoptotic pathways through transcriptomics STING activation causes T cell death independent of the IFN and validating in modified murine models. In the context of cancer pathway. We hypothesize that induction of STING leads to immunotherapy, better biological understanding of this pathway impaired proliferation and health in T cells due to activating informs how small molecule therapy can be utilized to promote its lesser known proton channel function. Here, we investigate tumor killing while still maintaining a patient’s adaptive immune how different branches of STING affect T cell health and population. InvestigatingHowCommensalGutBacteriaandTheirProductsPromoteAnti- Tumor Immunity Ashley Killian, Shumeng Hao, Francesca Gazzaniga University of California Berkeley | Molecular and Cellular Biology | 2027 Why some cancer patients respond to immunotherapy while isolates, E. ramosum consistently induced the highest T cell others do not remains a major clinical challenge. Emerging proliferation and cytotoxic cytokine production. Furthermore, evidence points to the gut microbiome as a critical factor, yet theRNA sequencing analysis also confirmed upregulation of IL-2, underlying mechanisms are not fully understood. We identified IFN-γ, and other cytotoxicity-related genes in E. ramosum-treated a commensal bacterium, Erysipelatoclostridium ramosum, that T cells. Mechanistically, this effect was blocked by an NF-κB overcomes microbiome-dependent resistance to immunotherapy in inhibitor, but not by inhibitors of JNK, ERK, p38, PI3K, or AKT, mice. Analysis of tumor-infiltrating immune cells revealed that E. indicating NF-κB-dependent signaling. These results suggest that ramosum colonization significantly increased proliferating CD8+ E. ramosum potently stimulates CD8+ T cell proliferation and T cells, as measured by Ki67 staining. To assess direct effects, cytotoxic activity, with evidence pointing to upregulation of NF- we treated isolated CD8+ T cells with E. ramosum pellets or κB signaling. In the future, E. ramosum may serve as a promising supernatants; only the pellets enhanced CD8+ T cell proliferation microbial approach to enhance anti-tumor immunity and improve and cytotoxicity in vitro. In a screen of 22 human gut bacterial immunotherapy outcomes. 6 Harvard-Amgen Scholars Program AnAlzheimer'sDiseaseRiskVariant ofTREM2ConfersSex-SpecificChanges in Adult Hippocampal Neurogenesis Sophia Kouznetsov, Ryan W. Castro, Se Hoon Choi Worcester Polytechnic Institute | Neuroscience | 2026 Alzheimer’s disease (AD) is a progressive neurodegenerative differentiation, and survival of NPCs, in 4-month-old male and disorder, affecting over 55 million people globally. The female mice (N = 5 per group) harboring wild-type TREM2, hippocampus, a central structure in learning and memory, is full TREM2 gene knockout, or the TREM2-R47H mutation, severely affected in AD, where impaired adult hippocampal which is the most prevalent and widely studied TREM2-mutation neurogenesis (AHN) contributes to the marked cognitive decline. that confers increased AD risk. While no genotype-specific AHN occurs in the dentate gyrus, where neural stem cells can effects were observed in proliferation or differentiation, female self-renew or differentiate into neural progenitor cells (NPCs), R47H mice exhibited increased NPC survival, suggesting a sex- eventually giving rise to mature granule neurons or glia. This specific vulnerability. Premature differentiation and subsequent process declines with age and is further disrupted in AD due depletion of the stem cell reserve are common hallmarks of to mechanisms that are yet to be fully understood. Variants AD, and the higher prevalence of AD in females is well in the immune-modulatory gene TREM2 — Triggering Receptor described. Thus, the current findings highlight a possible link Expressed on Myeloid Cells 2 — which is expressed primarily between microglial dysfunction driven by TREM2 mutations and by microglia in the central nervous system, confer up to a four- impaired neurogenesis in AD. Targeting TREM2 may offer a dual fold risk of developing AD. Due to the emerging role of microgliatherapeutic approach, modulating inflammation and supporting as regulators of AHN, understanding the role of this microglia- neurogenesis, improving cognitive outcomes beyond current specific AD risk factor in AHN regulation is imperative. Thus, plaque-targeting strategies. we quantified facets of neurogenesis, namely the proliferation,
Source:
Harvard / Harvard-Amgen Scholars Program 5 / 2025
Topics:
cell, sting, proliferation, ramosum, trem2, neurogenesi, mechanism, immune, tumor, anti, pathway, ifn
