Easy IMMUNO-ATMPs’ Post

I recently delved into a review on the role of Tumor-Infiltrating T Cells and Immunotherapy in hepatocyte carcinoma (HCC) and wanted to share some details that might interest fellow immunologists. 📚✨ 🔬 Deep Dive into Tumor Microenvironment (TME) and Immune Cell Roles: Intricate Immune Landscape: The liver’s immune microenvironment involves a dynamic interplay between various immune cells and non-immune constituents. Key players include cytotoxic T cells (CTLs), regulatory T cells (Tregs), and natural killer (NK) cells. 🔬 Functional Roles of Key Immune Cells: 👉 CTLs: These cells are crucial for targeting and lysing tumor cells through the release of perforin and granzymes. Their efficacy, however, is often hampered by the immunosuppressive TME. 👉Tregs: Tregs contribute to immune tolerance but can impede effective anti-tumor responses in HCC. Their presence is often associated with poorer prognosis due to the suppression of CTL activity. 👉NK Cells: NK cells play a vital role in tumor surveillance and cytotoxicity. In HCC, their activity is often diminished by factors within the TME, such as PGE2 and IDO enzymes, leading to immune evasion. 🔬Immunosuppressive Components: 👉Cancer-Associated Fibroblasts (CAFs): Originating from hepatic stellate cells, CAFs contribute to tumor progression by secreting IL-6, HGF, VEGF, and angiopoietin-1, which enhance tumor growth and angiogenesis. 👉Liver Sinusoidal Endothelial Cells: These cells act as non-myeloid antigen-presenting cells and can induce CD8+ T-cell tolerance through cross-presentation, facilitating immune evasion by tumors. Immune Evasion Mechanisms: 🔬Metabolic Reprogramming: 👉Tumor-released metabolites such as S-adenosyl-L-methionine and methylthioadenosine alter chromatin accessibility in T cells, leading to T-cell exhaustion. 👉Immune Checkpoints: The upregulation of PD-1, CTLA-4, and Lag-3 on T cells within the TME marks a significant barrier to effective immune responses. This review highlights the importance of targeting these checkpoints to rejuvenate T-cell function. 🌟 Future Directions: Combination Therapies: The review underscores the potential of combining ICIs with antiangiogenic agents or locoregional therapies to overcome immune barriers and enhance anti-tumor responses. 🌟 Innovative Therapies: The potential of CAR-T and TCR-T cell therapies in targeting tumor-associated antigens (TAAs) like GPC-3 and AFP is explored, offering new hope despite current challenges in solid tumors. 🔗 This comprehensive review offers invaluable insights into the TME of HCC and emerging therapeutic strategies. https://lnkd.in/eSfRijSW

Raghavendra Basavaraja et al. PARP11 inhibition inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies. Cell Repirts Medicine, VOLUME 5, ISSUE 7, 101649, JULY 16, 2024 DOI:https://lnkd.in/dYqE8_Q3 "Highlights • Tumor-derived factors upregulate PARP11 in the tumor-infiltrating Treg cells • PARP11 supports the immunosuppressive properties of Treg cells • Pharmacologic inhibition of PARP11 inactivates intratumoral Treg cells • PARP11 inhibitor augments the efficacy of immunotherapies Summary Tumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenvironment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here, we demonstrate that poly-(ADP-ribose)-polymerase-11 (PARP11) is an essential regulator of immunosuppressive activities of TI-Tregs. Expression of PARP11 correlates with TI-Treg cell numbers and poor responses to immune checkpoint blockade (ICB) in human patients with cancer. Tumor-derived factors including adenosine and prostaglandin E2 induce PARP11 in TI-Tregs. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivates TI-Tregs and reinvigorates anti-tumor immune responses. Accordingly, ITK7 decelerates tumor growth and significantly increases the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of chimeric antigen receptor (CAR) T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies."

Researchers at UCLA have uncovered a potent one-two punch against deadly brain cancers called malignant gliomas in a PICI-funded study newly published in Nature Communications. PICI Investigators including Robert Prins, PhD, combined a personalized dendritic cell vaccine with the immune boosting agent poly-ICLC, delivering a significantly amplified anti-tumor immune response. Adding poly-ICLC induced a substantially stronger immune response than the vaccine alone; it boosted interferon and antigen presentation genes, along with activating key immune cells like monocytes, CD4+ and cytotoxic CD8+ T cells primed to attack the cancer. Notably, the degree of this poly-ICLC-driven immune activation directly correlated with delayed tumor progression and prolonged overall survival, suggesting its potential as a predictive biomarker. Imaging data from long-term survivors further corroborated an enhanced anti-tumor immune environment following the combination therapy. Based on these findings, the UCLA team concluded that pairing poly-ICLC with the dendritic cell vaccine creates ideal conditions to unleash a robust anti-glioma response. While these findings are promising, larger confirmatory studies are needed to evaluate this dual #immunotherapy approach – potentially incorporating immune checkpoint inhibitors – against these aggressive brain malignancies. Congratulations to the team on this important step forward for a critical patient population. Read the Nature publication: https://lnkd.in/eVy45VeE Read more from UCLA: https://lnkd.in/eGvaK35C

Acquisition of suppressive function by conventional T cells limits antitumor immunity upon Treg depletion Regulatory T (Treg) cells contribute to immune homeostasis but suppress immune responses to cancer. Strategies to disrupt Treg cell–mediated cancer immunosuppression have been met with limited clinical success, but the underlying mechanisms for treatment failure are poorly understood. By modeling Treg cell–targeted immunotherapy in mice, we find that CD4+ Foxp3− conventional T (Tconv) cells acquire suppressive function upon depletion of Foxp3+ Treg cells, limiting therapeutic efficacy. Foxp3− Tconv cells within tumors adopt a Treg cell–like transcriptional profile upon ablation of Treg cells and acquire the ability to suppress T cell activation and proliferation ex vivo. Suppressive activity is enriched among CD4+ Tconv cells marked by expression of C-C motif receptor 8 (CCR8), which are found in mouse and human tumors. Upon Treg cell depletion, CCR8+ Tconv cells undergo systemic and intratumoral activation and expansion, and mediate IL-10–dependent suppression of antitumor immunity. Consequently, conditional deletion of Il10 within T cells augments antitumor immunity upon Treg cell depletion in mice, and antibody blockade of IL-10 signaling synergizes with Treg cell depletion to overcome treatment resistance. These findings reveal a secondary layer of immunosuppression by Tconv cells released upon therapeutic Treg cell depletion and suggest that broader consideration of suppressive function within the T cell lineage is required for development of effective Treg cell–targeted therapies. https://lnkd.in/eSqt9FuQ

#Immunotherapy | #VaxInnate: Improving Therapeutic #Cancer #Vaccines by modulating #Tcells & the #TumorMicroEnvironment | Breaking 'Perspective' at Nature Reviews #Immunology from Faezzah Baharom et al | #neoantigens | T cells have a critical role in mediating antitumour immunity. The success of immune checkpoint inhibitors (ICIs) for cancer treatment highlights how enhancing endogenous T cell responses can mediate tumour regression. However, mortality remains high for many cancers, especially in the metastatic setting. Based on advances in the genetic characterization of tumours and identification of tumour-specific antigens, individualized therapeutic cancer vaccines targeting mutated tumour antigens (neoantigens) are being developed to generate tumour-specific T cells for improved therapeutic responses. Early clinical trials using individualized neoantigen vaccines for patients with advanced disease had limited clinical efficacy despite demonstrated induction of T cell responses. Therefore, enhancing T cell activity by improving the magnitude, quality and breadth of T cell responses following vaccination is one current goal for improving outcome against metastatic tumours. Another major consideration is how T cells can be further optimized to function within the tumour microenvironment (TME). In this Perspective*, Faezzah Baharom, Dalton Hermans, Lélia Delamarre & Robert Seder focus on neoantigen vaccines and propose a new approach, termed Vax-Innate, in which vaccination through intravenous delivery or in combination with tumour-targeting immune modulators may improve antitumour efficacy by simultaneously increasing the magnitude, quality and breadth of T cells while transforming the TME into a largely immunostimulatory environment for T cells. *https://lnkd.in/eqQJidQg Celentyx Ltd #immunooncology #drugdiscovery www.celentyx.com Professor Nicholas Barnes PhD, FBPhS Omar Qureshi Catherine Brady FIGURE | ‘Vax-Innate’ strategy may improve neoAg cancer vaccines for advanced disease | The optimal strategy for therapeutic cancer vaccines is highly dependent on the tumour setting. a, In the adjuvant setting, a patient has undergone surgery to remove most or all of their solid tumour. At this stage, the tumour may be more homogeneous and contains a less suppressive or absent tumour microenvironment (TME). Based on these factors, there may be a lower threshold for the magnitude of T cell responses to eliminate any residual tumour or prevent tumour from being established over time. b, In the advanced setting, wherein a patient has advanced and/or metastatic disease, more robust therapy is probably required to combat the heavy tumour burden composed of heterogeneous tumour populations and highly suppressive TMEs. For these tumours, a high magnitude of quality T cells with greater breadth alongside innate stimuli acting to improve TME-driven immunosuppression will probably be required to achieve therapeutic responses |

🌟 𝐔𝐧𝐝𝐞𝐫𝐬𝐭𝐚𝐧𝐝𝐢𝐧𝐠 𝐓𝐮𝐦𝐨𝐫 𝐈𝐦𝐦𝐮𝐧𝐨𝐥𝐨𝐠𝐲 🌟 🔴 The Battle Between the Immune System and Cancer Cells 🧫 This cartoon-style diagram is a fun and simplified depiction of the key players involved in tumor immunology, showcasing the interactions between immune cells and tumor cells. Here’s a breakdown of the main components: 1. Tumor Cells (center): The large mass in the center represents a growing tumor. 2. CD8 Cytotoxic T cells (bottom right): These are represented as cells with swords. They are responsible for killing tumor cells by releasing perforin and other cytotoxic molecules (perforin sword), but their action can be blocked by inhibitory signals like PD-L1 (on the tumor cells). 3. CD4 Helper T cells (left and right): These cells help direct the immune response by releasing cytokines like IFN-γ, which stimulates other immune cells, including cytotoxic T cells and natural killer (NK) cells. 4. Dendritic Cells (bottom left): Shown as cells presenting antigens to other immune cells, these are responsible for “sounding the alarm” to initiate the immune response by presenting tumor antigens to T cells. 5. Regulatory T cells (top right and bottom right): These are shown with police hats, representing their role in suppressing the immune response. They protect the tumor by inhibiting the activity of cytotoxic T cells and other immune cells, allowing the tumor to evade immune destruction. 6. Exhausted T Cells (bottom center): These cells appear fatigued and inactive. They represent a state in which T cells lose their ability to effectively attack the tumor, often due to chronic exposure to tumor antigens and inhibitory signals like PD-1/PD-L1. 7. B Cells (bottom left): Depicted as shooting antibodies toward the tumor, B cells produce tumor-specific antibodies that can help flag tumor cells for destruction by other immune cells. 8. Natural Killer (NK) Cells (center left): These cells are equipped with "weapons" like TNF and IFN-γ and can kill tumor cells directly without needing prior sensitization, making them an important part of the innate immune response. 9. Myeloid-derived Suppressor Cells (MDSCs) (bottom center): These cells suppress the immune response, including T cells and NK cells, contributing to tumor immune evasion. 10. Inactivated T cells (bottom center): Shown as unarmed, these T cells have been rendered ineffective, possibly by tumor-induced immune suppression mechanisms such as PD-L1 or TGF-β. 11. Suppressive Dendritic Cells (bottom right): These cells, like the MDSCs, contribute to an immunosuppressive environment, helping protect the tumor from the immune system. Aiming to boost the immune system’s ability to identify and destroy cancer cells. With advances in research, therapies like checkpoint inhibitors, #CAR-T cells, and cancer vaccines are showing great promise. picture source : cell cartoon #Tumor_immunology #Biotechnology

How to kill cancer without killing your gut❓❓ 🤔 🔴 If you are interested in immunotherapy, you might have heard of the severe side effects that some patients experience, such as colitis. Colitis is a painful inflammation of the digestive tract that can make some patients stop their cancer treatment. 😢 🔴 But what if there was a way to deliver immunotherapy's cancer-killing impact without the unwelcome side effect? 🙌 That's what a team of researchers at the University of Michigan Rogel Cancer Center, led by Dr. Gabriel Núñez and Dr. Bernard Lo have achieved in a recent study. 🔴 They discovered that the composition of the gut microbiota, the bacteria that live in our intestines, plays a crucial role in causing colitis from immune checkpoint inhibitors, a type of immunotherapy that unleashes the immune system to attack cancer cells. 🔥 🔴 By using a new mouse model that mimics the human gut microbiota, they identified a specific domain of the immune checkpoint antibodies that triggers the hyper-activation of immune T cells and the deletion of regulatory T cells, which normally keep the immune system in check. 🧬 🔴 They then removed that domain from the antibodies and found that they could still achieve a strong anti-tumor response but without inducing colitis. 🎉 🔴 This is the first time that microbiota are proven to be essential for developing colitis from immune checkpoint inhibition, and the first time that a modified antibody is shown to prevent colitis while preserving the anti-tumor effect. 💯 🔴 The researchers also confirmed their findings in human cells from patients treated with immune checkpoint antibodies, which showed the same role of regulatory T cells in inducing colitis. 🧪 🔴 The antibody they used to stop the colitis was developed by TAKEDA PHARMACEUTICALS AMERICA, INC., and the researchers are now seeking clinical partners to move this knowledge to a clinical trial. 💊 This research is a game-changer for immunotherapy, as it could improve the quality of life and the survival rate of cancer patients . 🙏 It also shows the importance of understanding the mechanisms behind the side effects of immunotherapy, and how to develop alternative therapies that are more beneficial. Link to the full paper is below. https://lnkd.in/dgetzkew If you found this post interesting and informative, don't forget to like it. 😉 #immunotherapy #cancer #colitis #microbiota #currentresearch #science #health #medicine #nature #immunology #rogelcancercenter #takeda #antibody #linkedin #molecularbiology

Ryba-Stanisławowska, M. Unraveling Th subsets: insights into their role in immune checkpoint inhibitor therapy. Cell Oncol. (2024). https://lnkd.in/dMpZV9gQ "Abstract T helper (Th) cell subsets play pivotal roles in regulating immune responses within the tumor microenvironment, influencing both tumor progression and anti-tumor immunity. Among these subsets, Th1 cells promote cytotoxic responses through the production of IFN-γ, while Th2 cells and regulatory T cells (Tregs) exert immunosuppressive effects that support tumor growth. Th9 and Th17 cells have context-dependent roles, contributing to both pro-inflammatory and regulatory processes in tumor immunity. Tumor antigen-specific T cells within the tumor microenvironment often exhibit a dysfunctional phenotype due to increased expression of inhibitory receptors such as CTLA-4 and PD-1, leading to reduced antitumor activity. Monoclonal antibodies that block these inhibitory signals—collectively known as immune checkpoint inhibitors (ICIs)—can reactivate these T cells, enhancing their ability to target and destroy cancer cells. Recent advancements have highlighted the critical role of T helper subsets in modulating responses to ICIs, with their interactions remaining a focus of ongoing research. Both positive and negative effects of ICIs have been reported in relation to Th cell subsets, with some effects depending on the type of tumor microenvironment. This review summarizes the crucial roles of different T helper cell subsets in tumor immunity and their complex relationship with immune checkpoint inhibitor therapy." https://lnkd.in/dNaY4Fyc

🔬 Decoding the Tumor Microenvironment: The Immune System's Role in Cancer Progression 🌱 Did you know that within every tumor lies a complex battlefield, where your immune system either fights to eradicate the cancer or, in some cases, is co-opted to help the tumor survive? 💥 Pro-Tumor Killing Forces: 💪 Several immune cells are central to the body’s natural ability to identify and destroy cancerous cells: Natural Killer (NK1) Cells & NKT1 Cells are crucial first responders, releasing cytotoxic molecules such as granzyme and perforin. These molecules target and induce apoptosis (programmed cell death) in tumor cells, effectively eradicating them. 💣 A subtype of T-helper cells, Th1 cells contribute by not only releasing granzyme and perforin but also secreting interferon-gamma (IFNγ), a key cytokine that amplifies the anti-tumor activity of other immune cells like macrophages and dendritic cells. ⚔️ M1 Macrophages are central to tumor elimination through phagocytosis, where they engulf and digest tumor cells. Additionally, M1 macrophages secrete tumor necrosis factor-alpha (TNFα) and other pro-inflammatory cytokines that stimulate further immune responses, reinforcing the immune attack. 💥 Dendritic Cells (DCs) are professional antigen-presenting cells (APCs) that play a pivotal role in initiating and sustaining anti-tumor immune responses by capturing tumor antigens and presenting them to T-cells, thereby orchestrating a broader immune attack. 🧠 Immune Suppression Forces: 🛡️ While these immune cells contribute to tumor eradication, the tumor microenvironment can also harbor immune-suppressive cells that promote tumor growth and survival: Regulatory T Cells (Tregs) produce immunosuppressive cytokines like IL-10 and TGF-β, which inhibit the activation and function of cytotoxic T-cells and NK cells, essentially dampening the immune response and allowing the tumor to evade immune detection. 🧪 Myeloid-Derived Suppressor Cells (MDSCs) secrete IL-18 and other factors that suppress the immune system by inhibiting effector T-cells and NK cells. This creates an immune-suppressive environment that shields the tumor from effective immune attacks, promoting its survival and growth. 🛡️ In contrast to their M1 counterparts, M2 macrophages support tumor growth by releasing IL-10 and TGF-β, both of which foster an immunosuppressive environment. These "alternatively activated" macrophages also facilitate tissue repair, but in the context of the TME, this can inadvertently support tumor progression. 🧬 Understanding these forces within the TME is crucial for designing effective cancer immunotherapies aimed at tipping the balance toward tumor eradication. #CancerResearch #Immunotherapy #TumorMicroenvironment #ScientificBreakthroughs *made through biorender.com*

𝐇𝐨𝐰 𝐓 𝐜𝐞𝐥𝐥 𝐊𝐢𝐥𝐥𝐬 𝐚 𝐂𝐚𝐧𝐜𝐞𝐫 𝐜𝐞𝐥𝐥? T cells, a crucial component of the immune system, play a pivotal role in recognizing and eliminating cancerous cells through a process known as cell-mediated immunity. When a T cell encounters a cancer cell, several intricate mechanisms come into play to orchestrate the destruction of the malignant invader. Firstly, T cells must recognize specific antigens present on the surface of cancer cells. Antigens are molecules that trigger an immune response, and cancer cells often display abnormal or mutated antigens, distinguishing them from healthy cells. T cells, equipped with specialized receptors called T cell receptors (TCRs), scan the surface of cells in search of these antigens. 𝐂𝐥𝐢𝐜𝐤 𝐇𝐞𝐫𝐞 𝐭𝐨 𝐆𝐞𝐭 𝐅𝐫𝐞𝐞 𝐏𝐃𝐅 𝐁𝐫𝐨𝐜𝐡𝐮𝐫𝐞: https://lnkd.in/gpJf3bk7 When a #TCR binds to a cancer-specific antigen presented by major histocompatibility complex (MHC) molecules on the surface of the cancer cell, a series of signaling events are initiated within the T cell, activating it to take action against the cancerous threat. Once activated, the T cell undergoes a remarkable transformation, transitioning into a cytotoxic T lymphocyte (CTL), armed with the ability to directly destroy cancer cells. CTLs release perforin and granzymes, two potent cytotoxic molecules, to initiate apoptosis, or programmed cell death, in the cancer cell. Perforin creates pores in the cancer cell's membrane, allowing granzymes to enter and induce apoptosis by activating #enzymes that dismantle the cell's internal structures. This process ensures the targeted destruction of the cancer cell while minimizing collateral damage to surrounding healthy tissue. Moreover, T cells can also deploy #cytokines, signaling proteins that regulate immune responses, to coordinate a broader anti-cancer immune reaction. Cytokines such as interferon-gamma stimulate other immune cells to join the fight against cancer and enhance the overall immune response. Additionally, memory T cells are generated during this process, providing long-term immunity against recurring cancer threats. These memory T cells retain information about the cancer-specific antigens, enabling a faster and more robust immune response upon subsequent encounters with the same cancer type. The intricate dance between T cells and cancer cells underscores the remarkable complexity and efficacy of the immune system in recognizing and eradicating malignancies. Through a combination of antigen recognition, activation, cytotoxicity, and memory formation, T cells serve as potent guardians of our health, relentlessly combating the threat of cancer. #Tcells #cancer #tcrcell #celltherapy #future #innovation #healthcare