Publications by authors named "Dennis Adeegbe"
Background: Evading immune surveillance is a hallmark for the development of multiple cancer types. Whether immune evasion contributes to the pathogenesis of high-grade prostate cancer (HGPCa) remains an area of active inquiry.
Methods: Through single-cell RNA sequencing and multicolor flow cytometry of freshly isolated prostatectomy specimens and matched peripheral blood, we aimed to characterize the tumor immune microenvironment (TME) of localized prostate cancer (PCa), including HGPCa and low-grade prostate cancer (LGPCa).
Article Synopsis
- Regulatory T cells (Tregs) in solid tumors are linked to poor patient outcomes and contribute to dysfunction in tumor-infiltrating CD8 +T cells by causing an "exhaustion-like" state.
- The study found that reducing Treg levels can reverse the dysfunction in CD8 +T cells, with a notable link to CTLA-4 expression by Tregs.
- Analysis showed that as tumors progressed, there was a decrease in the diversity of CD8 +T cell clones and reduced IL-2 levels, indicating that Treg accumulation reshapes the T cell repertoire and negatively impacts survival.
Article Synopsis
- The focus of existing research on KLRG1 has mainly been on NK and CD8 T cells, while the implications for Tregs, especially the most suppressive ones expressing KLRG1, have been largely overlooked.
- This review examines current literature regarding KLRG1, particularly its role in Tregs during cancer development and autoimmunity.
- The authors suggest that when creating anti-tumor therapies targeting KLRG1, it’s crucial to consider how these therapies impact both effector cells and regulatory T cells.
Article Synopsis
- HDAC6 inhibitor Citarinostat (ACY241) boosts T cell activity and macrophage function in lung tumors, promoting effective immune responses.
- ACY241 treatment leads to genomic changes in tumor-associated T cells and macrophages that improve T cell viability and reduce inhibitory signals.
- Combining ACY241 with the chemotherapy drug Oxaliplatin significantly enhances the immune response against lung cancer, suggesting a potential new therapy for non-small cell lung cancer (NSCLC).
Article Synopsis
- Ultraviolet radiation exposure is a known risk factor for cutaneous squamous cell carcinoma (cuSCC) and is linked to increased levels of immunosuppressive regulatory T cells (Tregs).
- This study aimed to evaluate whether higher levels of specific Tregs, particularly CCR4, are associated with the development of cuSCC in individuals exposed to high levels of UVR.
- Results indicated that individuals with elevated circulating CCR4 Tregs at baseline have a significantly increased risk of developing cuSCC, especially those exposed to high UVR, highlighting the potential for these Tregs as indicators for skin cancer risk and future research opportunities.
Article Synopsis
- Immunotherapy (IT) combined with targeted therapy (TT) can treat melanoma, but their combination often leads to toxicity; the study explores whether a specific treatment order (IT followed by TT) is beneficial.
- Mouse models with different types of mutant melanomas were treated with IT, TT, or the IT→TT sequence to assess tumor response and immune changes.
- Results showed that the IT→TT sequence enhanced T-cell infiltration, altered the immune environment, and improved therapeutic outcomes by preventing tumor evasion, highlighting that initial IT can enhance the effectiveness of subsequent TT.
Article Synopsis
- A study identified distinct molecular subtypes of muscle-invasive bladder cancer (MIBC) that respond differently to cisplatin-based chemotherapy and PD-L1 immunotherapy.
- Researchers performed an analysis on 388 MIBC samples to establish a 42 gene panel that helps classify these subtypes into basal and luminal types, with implications for patient treatment strategies.
- The findings highlighted that the basal subtype has worse survival without chemotherapy but better outcomes with it, and patients with low expression of specific genes had lower response rates to immunotherapy and worse overall survival.
Article Synopsis
- Unconventional T-lymphocyte populations, specifically innate αβ T cells (iαβTs), play a significant role in regulating tumor immunity, particularly in pancreatic ductal adenocarcinoma (PDA).
- iαβTs make up around 10% of T lymphocytes in PDA and have unique T-cell receptor profiles and immunogenic characteristics compared to other lymphocytes.
- The study demonstrates that iαβT cells not only help slow tumor growth through adoptive transfer in both mouse and human models but also promote the activation and expansion of other immune cells, marking them as promising targets for immunotherapy.
Article Synopsis
- Anti-CTLA-4 monoclonal antibodies (mAb) improve tumor immunity in humans by selectively targeting T cell populations, particularly differentiation between suppressive Treg and activating CD8 T cells.
- High-ADCC/ADCP anti-CTLA-4 mAb can effectively deplete FOXP3 Treg cells while promoting the expansion of tumor-specific CD8 T cells, especially when antigen exposure is delayed after mAb treatment.
- The study highlights the importance of antibody modification and timing in enhancing immune responses in cancer therapy, opening pathways for future immunotherapy designs.
Article Synopsis
- Pancreatic ductal adenocarcinoma (PDA) is resistant to immunotherapy and shows immune tolerance, making treatment challenging.
- Researchers identified an increased level of RIP1 in tumor-associated macrophages in PDA and developed a specific RIP1 inhibitor that effectively targets these macrophages.
- Inhibiting RIP1 leads to enhanced immune responses by activating cytotoxic T cells and promoting a beneficial immune environment, suggesting that targeting RIP1 could improve immunotherapy outcomes for PDA.
Article Synopsis
- Tumor mutational burden is linked to how well tumors respond to immune checkpoint therapy, but this connection is unclear in microsatellite-stable tumors.
- An analysis of 249 tumors and their normal tissue identified additional genomic factors influencing therapy response, including specific driver gene mutations and neoantigens, beyond just mutational burden.
- The findings emphasize the complexity of tumor genetics in creating an immunoresponsive environment and suggest a need for comprehensive analysis of large clinical data to find reliable predictive indicators for treatment response.
Article Synopsis
- Researchers used computer modeling to find neoepitopes, which are new immune targets, coming from intron retention events in tumor RNA.
- The study demonstrated through mass spectrometry that these retained intron neoepitopes are effectively processed and displayed on MHC I molecules in cancer cells.
- The findings suggest that these RNA-derived neoepitopes could play a significant role in developing personalized cancer vaccines in the future.
Article Synopsis
- Mutations in the KRAS gene are found in about 30% of lung adenocarcinomas, making treatment challenging due to tumor resistance and immunosuppressive factors.
- Recent studies show that combining BET bromodomain inhibitors, like JQ1, with PD-1 antibodies can enhance the immune response against tumors by reducing regulatory T cells and activating T cells more effectively.
- This combination therapy resulted in significant and lasting antitumor effects in mouse models, suggesting a potential new treatment strategy for lung adenocarcinoma and other solid tumors.
Article Synopsis
- Some agents targeting downstream signaling pathways, like MEK inhibitors, are being developed to address the challenges of directly targeting mutant KRAS in lung cancer, but their effectiveness in combination with chemotherapy is still debated.
- A new genetically engineered mouse model mimicking the most common KRAS mutation in lung cancer shows that KRAS tumors respond better to treatment with selumetinib, a MEK inhibitor, compared to other tumor types.
- The study reveals that the presence of mutations in tumor-suppressor genes, like p53, affects the sensitivity of KRAS lung tumors to treatments, suggesting that specific genetic profiles should guide therapy options for lung cancer patients.
Article Synopsis
- * Researchers conducted a synthetic lethal screen that revealed HDAC6 as a promising target when paired with the BET inhibitor JQ1, hinting at a new treatment approach.
- * The combination of the HDAC6 inhibitor ricolinostat and JQ1 significantly reduced tumor growth, with evidence showing that NK cells are crucial for the effectiveness of this combined treatment.
Article Synopsis
- The study examines the role of the MUC1-C oncoprotein in non-small cell lung cancer (NSCLC) and its impact on the immune microenvironment, particularly how it relates to PD-L1 and immune suppression.
- Using a mouse model, researchers found that inhibiting MUC1-C with GO-203 reduced PD-L1 levels and increased the activity of CD8+ T-cells, which are essential for immune response against tumors.
- The findings suggest that targeting MUC1-C could enhance the effectiveness of immunotherapy for NSCLC by improving the activation of tumor-fighting T-cells and could serve as a strategy for modifying the tumor environment in a positive way.
Article Synopsis
- Therapies for non-small cell lung cancer (NSCLC) are challenging, but understanding oncogenic pathways has led to better therapeutic approaches that enhance the immune response against tumors.
- This study focused on two drug classes, HDAC inhibitors and bromodomain inhibitors, and found that the selective HDAC6 inhibitor, ricolinostat, improves T-cell activation and function while the bromodomain inhibitor, JQ1, reduces the suppressive effect of regulatory T cells.
- Combining these drugs showed significant antitumor effects in mouse models of lung adenocarcinomas, suggesting their potential as effective treatments for NSCLC by promoting better immune responses against cancer.
Article Synopsis
- The TCR repertoire of regulatory T cells (Tregs) displays significant diversity that may be crucial for maintaining self-tolerance, but its exact role is not fully understood.
- In experiments involving transfers into immune-deficient mice, narrowing the Treg TCR repertoire did not cause autoimmunity, but transferring Tregs from a single primary recipient did lead to autoimmune symptoms in new hosts.
- This study suggests that a diverse Treg TCR repertoire (approximately 8-11% variety) is essential for effectively suppressing autoreactive T cells, highlighting the adaptability of Tregs in response to self-antigens.
Article Synopsis
- Immune checkpoint blockade response in mesenchymal tumors is not well understood, but studying these cancers can help improve immunotherapy.
- A patient with metastatic uterine leiomyosarcoma achieved over two years of complete remission on pembrolizumab (anti-PD-1) treatment, prompting analysis of their tumors.
- The resistant tumor showed PTEN loss and lower levels of certain neoantigens, indicating these factors may contribute to resistance against PD-1 therapy, while the sensitive tumor had robust immune response markers.
Article Synopsis
- Regulatory T (Treg) cells are crucial for maintaining immune tolerance to self and preventing autoimmune responses.
- The study indicates that Treg cells can induce anergy (a state of unresponsiveness) in self-reactive human CD8(+) T cells, likely by influencing antigen-presenting cells' costimulatory activity.
- The presence of anergic T cells, which have a naïve phenotype and higher levels of inhibitory markers, was detected in healthy individuals, demonstrating a potential mechanism for maintaining self-tolerance against autoimmune conditions like vitiligo.
Article Synopsis
- CD4+Foxp3+ T regulatory (Treg) cells play a key role in regulating immune responses and maintaining balance, influencing conditions like autoimmune diseases, inflammation, and cancer.
- There are two types of Treg cells: natural (nTreg), which develop in the thymus and are crucial for peripheral tolerance, and induced (iTreg), which arise from conventional CD4+ T cells but have less clear characteristics.
- While Treg cells can suppress harmful immune responses to self-antigens, they can also hinder the immune system's attack on tumors; the review discusses their functions in both contexts, especially in relation to enhancing anti-tumor immunity.
Article Synopsis
- T regulatory cells (Tregs) help prevent the immune system from rejecting organ transplants (allografts) by promoting tolerance, which could reduce the need for immunosuppressive drugs.
- The research showed that for effective tolerance to occur, the Tregs must closely match the antigens of the grafts, although tolerance can also develop even if major histocompatibility complex (MHC) molecules are absent on the graft.
- The study suggested that maintaining this tolerance involves both the suppression of the immune response by Tregs and the elimination of reactive T cells in the thymus, underlying the importance of Tregs in successful transplantation.