Parker Institute for Cancer Immunotherapy’s Post

Novel Immunotherapy Target for Breast Cancer Although immune checkpoint inhibitors (ICIs) such as KEYTRUDA and OPDIVO represent a major advance in cancer treatment, many patients with highly aggressive triple-negative breast cancer don’t benefit from ICIs now available. In a new study published online on November 13 in Developmental Cell, Wenjun Guo, Ph.D., Xingxing Zang, Ph.D., and colleagues identified a novel immunosuppressive mechanism, used by de-differentiated stem-like tumor cells, that may account for breast-tumor resistance to ICI treatment. They found that the transcription factor SOX9 causes numerous copies of the protein B7x to sprout on the surface of stem-like tumor cells. B7x is a “checkpoint” protein that—by binding to and stimulating inhibitory receptors on immune cells—prevents those cells from attacking stem-like tumor cells. As a result, pre-malignant lesions are able to progress to aggressive and invasive cancer. In experiments involving mouse models resembling highly aggressive triple-negative breast cancer, the researchers found that therapeutically inhibiting B7x protein suppressed tumor growth and greatly improved the effectiveness of ICIs approved for breast cancer patients. The findings suggest that targeting the SOX9-B7x pathway could significantly improve breast cancer treatment. Dr. Guo is professor of cell biology and a member of the Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine at Einstein. Dr. Zang is professor of microbiology & immunology, of oncology, of medicine, and of urology, is the Louis Goldstein Swan Chair in Cancer Research at Einstein, and a member of the National Cancer Institute–designated Montefiore Einstein Comprehensive Cancer Center. #BreastCancer #immunecheckpointinhibitors #ICIs #cancer #MECC

Cancer stem-cell like cells…

A newly identified CAR-T cell therapy target, GRP78, could be key to treating solid tumors 🦠 St. Jude Children's Research Hospital has validated the 78-kDa glucose-regulated protein (GRP78) as a potential target for immunotherapy. This could be a game-changer for patients with brain and solid tumors. Scientists showed that GRP78 is abundantly expressed in various tumor types, including glioblastoma and triple-negative breast cancer, and GRP78-targeted CAR-T cells successfully killed many types of cancers in both cell and mouse models. Interestingly, resistant tumor cell types caused the CAR-T cells to express GRP78 on their own cell surface – tricking the cells into killing each other or giving up. While work is still at a very early stage, this is yet another exciting research development into solid tumor treatment. Going forward, we must think early about how we set up for scale, in order to meet the demand of these new indications. 🔍 Learn more about the study: https://lnkd.in/eqeut_A5 #advancedtherapies #celltherapy #genetherapy #biotechnology #manufacturingbrighterfutures

👨🔬👩🔬 How would you like to fight cancer with your own immune cells❓❓🤔 That's the idea behind CAR T-cell immunotherapy, a revolutionary approach that has shown remarkable results against leukemia. But what about brain and solid tumors, which are more difficult to treat? 🧠 A team of researchers led by Dr. Giedre Krenciute and Dr. Paulina Velasquez at St. Jude Children's Research Hospital have discovered a new target for CAR T cells that could potentially work against a wide range of cancers, including glioblastoma, osteosarcoma, breast cancer and Ewing sarcoma. The target is called GRP78, a protein that is highly expressed on many tumor cells but not on healthy ones. 🎯 Sounds promising, right? Well, there's a catch. 🔴 Some tumors have developed a clever way to evade the CAR T cells by making them express GRP78 as well. This causes the CAR T cells to either become inactive or kill each other, leaving the tumor unharmed. 😱 🔴 The research found that this resistance mechanism varies among different tumor types, and that there is no correlation between the level of GRP78 on the tumor and the response to CAR T-cell therapy. This means that GRP78 is a complex and challenging target, but also a very intriguing one. 🔬 🔴 The findings open new avenues for developing effective immunotherapies for brain and solid tumors. The researchers are now working on ways to overcome the resistance mechanism and enhance the activity of GRP78-targeted CAR T cells. 💪 This research is a game-changer for the field of cancer immunotherapy, as it reveals a novel target and a novel resistance mechanism that could be exploited for the benefit of patients. 🙌 Link to the full paper is below. https://lnkd.in/dWZMf-Mr #StJude #CARTcell #Immunotherapy #Cancer #GRP78 #Research #Science #Innovation #CurrentResearch #Tumor #CellReportsMedicine

Dendritic Cell Therapy Dendritic cell (DC) therapy is a type of immunotherapy that uses the body's own dendritic cells, which are essential for initiating and regulating immune responses, to fight cancer. Dendritic cells function as antigen-presenting cells can capture antigens from pathogens or tumors and present them to T cells, thereby activating the immune system against these targets. In DC therapy, dendritic cells are collected from the patient, usually through a blood draw. These cells are then cultured and matured in the laboratory under specific conditions to enhance their ability to present cancer-specific antigens. These antigens may come from the patient's tumor cells or may consist of synthetic peptides that represent known cancer markers. Once the dendritic cells are fully primed and loaded with tumor antigens, they are reintroduced into the patient's bloodstream. After reinfusion, these primed dendritic cells migrate to the lymph nodes, where they interact with T cells, presenting tumor antigens to them. This presentation triggers a powerful T cell response against tumor cells throughout the body. The goal is for the activated T cells to seek out and destroy cells bearing these antigens, specifically targeting and killing cancer cells. Dendritic cell therapy has shown promise in treating a variety of cancers, including prostate cancer, melanoma, and glioblastoma. While the use of dendritic cell therapy is still not as widespread as other forms of immunotherapy, ongoing research and clinical trials continue to refine and expand the potential of dendritic cell therapy, making it a promising option for cancer treatment that harnesses the body's own immune defenses. References [1] Theresa Murphy and Kenneth Murphy, Cellular and Molecular Immunology 2022 (https://lnkd.in/eHCrxm3E) [2] Ignacio Heras-Murillo et al., Nature Reviews Clinical Oncology 2024 (https://lnkd.in/e5Cfrk6T) #DendriticCellTherapy #CancerTreatment #Immunotherapy #OncologyInnovation #ProstateCancer #Melanoma #HealthcareTechnology #MedicalResearch #FutureOfMedicine #CancerCare

Ortega, M.A., Boaru, D.L., De Leon-Oliva, D. et al. PD-1/PD-L1 axis: implications in immune regulation, cancer progression, and translational applications. J Mol Med (2024). https://lnkd.in/dfN9Wymd "The authors provide a comprehensive overview of the functions of the PD-1/PD-L1 system in immune function, cancer, and the potential therapeutic implications of the PD-1/PD-L1 pathway for cancer management. [Journal of Molecular Medicine]" "Abstract The PD-1/PD-L1 axis is a complex signaling pathway that has an important role in the immune system cells. Programmed cell death protein 1 (PD-1) acts as an immune checkpoint on the T lymphocytes, B lymphocytes, natural killer (NK), macrophages, dendritic cells (DCs), monocytes, and myeloid cells. Its ligand, the programmed cell death 1 ligand (PD-L1), is expressed in the surface of the antigen-presenting cells (APCs). The binding of both promotes the downregulation of the T cell response to ensure the activation to prevent the onset of chronic immune inflammation. This axis in the tumor microenvironment (TME) performs a crucial role in the tumor progression and the escape of the tumor by neutralizing the immune system, the engagement of PD-L1 with PD-1 in the T cell causes dysfunctions, neutralization, and exhaustion, providing the tumor mass production. This review will provide a comprehensive overview of the functions of the PD-1/PD-L1 system in immune function, cancer, and the potential therapeutic implications of the PD-1/PD-L1 pathway for cancer management." https://lnkd.in/di-WtCWU

Just released: Our newest publication in Journal of Pathology   We are proud to inform you that our review about tumor immunology entitled:   “Spatial analyses of immune cell infiltration in cancer: Current methods and future directions. A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer”   has now been successfully published.   In this review by David B Page, we give an overview of two approaches for reporting and analyzing spatial data (raster versus vector-based). We provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers.   Two well-described clinical biomarkers, the Breast Cancer stromal tumor infiltrating lymphocytes score and the Colon Cancer Immunoscore are discussed. Furthermore investigative opportunities to improve clinical utility of these spatial biomarkers are described. Read more about it: https://lnkd.in/eJvdAtBV   #biomarker #BreastCancer #immunology #GBGForschungs

🔬 Lung cancer is a complex disease in which the tumour microenvironment plays a critical role and macrophages are intimately involved in the progression of the disease. In order to better understand the intricate interplay and dynamic relationship between lung cancer and macrophages, a team led by researchers at the Wellcome Sanger Institute used the PhenoCycler-Fusion and other technology to profile approximately 900,000 cells from 25 treatment-naive patients with adenocarcinoma and squamous-cell carcinoma. They noted several things, including: 🔹 an inverse relationship between anti-inflammatory macrophages and NK cells/T cells, and with reduced NK cell cytotoxicity within the tumor; 🔹significant differences in the co-expression of various immune checkpoint inhibitors; 🔹evidence of a transcriptional “reprogramming” of macrophages in tumors, shifting them towards cholesterol export and adopting a fetal-like transcriptional signature which promotes iron efflux. The multi-omic resource offers a high-resolution molecular map of tumor-associated macrophages and an atlas of immune and non-immune compartments in lung cancer, in the hopes that it might inform efforts to develop more effective therapeutic strategies. 📚 Marco De Zuani, et al. Nature Communications: https://lnkd.in/gVNbsRgc #FridayRead #LUAD #LUSC, #NSCLC #lcsm #lungcancer #immunology #oncology #spatialbiology #PhenoCyclerFusion

Happy Friday all! Check out this new Nature Reviews Cancer article by Meier et al., "Immunogenic cell death in cancer: targeting necroptosis to induce antitumour immunity." Abstract: Most metastatic cancers remain incurable due to the emergence of apoptosis-resistant clones, fuelled by intratumour heterogeneity and tumour evolution. To improve treatment, therapies should not only kill cancer cells but also activate the immune system against the tumour to eliminate any residual cancer cells that survive treatment. While current cancer therapies rely heavily on apoptosis — a largely immunologically silent form of cell death — there is growing interest in harnessing immunogenic forms of cell death such as necroptosis. Unlike apoptosis, necroptosis generates second messengers that act on immune cells in the tumour microenvironment, alerting them of danger. This lytic form of cell death optimizes the provision of antigens and adjuvanticity for immune cells, potentially boosting anticancer treatment approaches by combining cellular suicide and immune response approaches. In this Review, we discuss the mechanisms of necroptosis and how it activates antigen-presenting cells, drives cross-priming of CD8+ T cells and induces antitumour immune responses. We also examine the opportunities and potential drawbacks of such strategies for exposing cancer cells to immunological attacks. #drugdiscovery #celldeath #necroptosis #cancerresearch #immunooncology #tme #scientificresearch

🟨🟪𝙏𝙪𝙢𝙤𝙧 𝙢𝙞𝙘𝙧𝙤𝙚𝙣𝙫𝙞𝙧𝙤𝙣𝙢𝙚𝙣𝙩 𝙧𝙚𝙢𝙤𝙙𝙚𝙡𝙞𝙣𝙜 𝙫𝙞𝙖 𝙩𝙖𝙧𝙜𝙚𝙩𝙚𝙙 𝙙𝙚𝙥𝙡𝙚𝙩𝙞𝙤𝙣 𝙤𝙛 𝙈2-𝙡𝙞𝙠𝙚 𝙩𝙪𝙢𝙤𝙧-𝙖𝙨𝙨𝙤𝙘𝙞𝙖𝙩𝙚𝙙 𝙢𝙖𝙘𝙧𝙤𝙥𝙝𝙖𝙜𝙚𝙨 𝙛𝙤𝙧 𝙘𝙖𝙣𝙘𝙚𝙧 𝙞𝙢𝙢𝙪𝙣𝙤𝙩𝙝𝙚𝙧𝙖𝙥𝙮 #MD_Immunol https://lnkd.in/dDUBnbbJ 🟪 Anti-tumor M1-like and pro-tumor M2-like tumor-associated macrophages (TAMs) coexist in #tumor #microenvironments (TME). 🟪 The adverse effects of these M1/M2 subsets on tumors directly affect the current strategies to improve anti-tumor immune response. Therefore, it has attracted great attention to change the tumor immunosuppressive microenvironment by reprogramming TAMs. 🟪 M2-like #macrophages represent most of TAMs in many cancer indications, which is associated with poor prognosis in several cancer patients, consistent with their abilities to favor tumor growth, to #promote #cancer #invasion and #metastasis. 🟪 M2 macrophages act as tumor promoters in several ways: 🔶️ Promoting cancer cell proliferation and invasion. 🔶️ In contrast to M1-like macrophages, NO and iNOS production appears diminished after TAMs switch to an M2-like phenotype leading to abolishment of M1 direct killing of tumor cells . 🔶️ Promoting angiogenesis. 🔶️ Dampening the activity of tumor killer cells. 🔶️ Promoting resistance to therapy. 🔶️ Hence, high proportion of M2-like macrophages in TAMs might be a causative factor for poor prognosis and shorter survival of patients in several cancers such as chronic lymphocytic leukemia , T cell leukemia/lymphoma , oral cancer, thyroid cancer. 🟪 The #mechanism of action of targeted depletion of M2-like TAMs involves: 🔶️ The transformation of M2-like macrophages to M1-like macrophages is sufficient to cause a tumor-suppressive polarization of macrophages, which can restrain tumor metastasis and promote immune cell infiltration. 🔶️ M1-like macrophages can suppress tumor angiogenesis, leading to reduced blood supply to tumor cells and impaired tumor growth. 🔶️ M1 macrophages can present antigens and activate adaptive immune responses, leading to the activation of T cells and the production of inflammatory cytokines. 🔶️ A higher density of M2-type macrophages is associated with increased tumor cell proliferation and vascularity, which can be reduced by targeted depletion of M2-like TAMs. 🔶️ The repolarization of macrophages from M2-like to M1-like macrophages can promote the maturation and activation of M0-like and M1-like cells, leading to a stronger antitumor immune response. 🟪 Current treatment strategies for targeting M2-like tumor-associated macrophages (TAMs) include: 🔶️ Limiting monocyte recruitment 🔶️ Depleting TAMs: deplete M2-like TAMs 🔶️ Reprogramming TAMs: Therapies that can reprogram M2-like TAMs to adopt an M1-like phenotype. 🔶️ Targeting inhibitory molecules: inhibitory molecules can increase TAM-mediated phagocytosis, which can help in tumor cell elimination. #immunology