bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–04–07
29 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Reprogramming of tumor-associated macrophages by metabolites generated from tumor microenvironment.
  2. Effect of acute inflammatory reaction induced by biopsy on tumor microenvironment.
  3. Cellular plasticity in the breast cancer ecosystem.
  4. Biophysical and biochemical aspects of immune cell-tumor microenvironment interactions.
  5. In vitro generation of murine myeloid-derived suppressor cells from hematopoietic progenitor cells.
  6. Extracellular vesicle-mediated communication between CD8+ cytotoxic T cells and tumor cells.
  7. Tumor-Host Cometabolism Collaborates to Shape Cancer Immunity.
  8. Navigating tumor angiogenesis: therapeutic perspectives and myeloid cell regulation mechanism.
  9. Disruption of CD47-SIRPα signaling restores inflammatory function in tumor-associated myeloid-derived suppressor cells.
  10. Assessment of myeloid-derived suppressor cell differentiation ex vivo.
  11. The value of intratumoral microbiota in the diagnosis and prognosis of tumors.
  12. Targeting methionine metabolism in cancer: opportunities and challenges.
  13. Tumor microenvironment immunomodulation by nanoformulated TLR 7/8 agonist and PI3k delta inhibitor enhances therapeutic benefits of radiotherapy.
  14. Nanoparticles in tumor microenvironment remodeling and cancer immunotherapy.
  15. Isolation and immunosuppressive functions of myeloid-derived suppressor cell-derived exosomes.
  16. Characterization of lysosomal acid lipase in Ly6G+ and CD11c+ myeloid-derived suppressor cells.
  17. Cancer-associated fibroblasts: protagonists of the tumor microenvironment in gastric cancer.
  18. Efficient combination of radiotherapy and CAR-T - A systematic review.
  19. In vitro osteoclastogenesis assessment using murine myeloid-derived suppressor cells.
  20. Integrative spatial omics reveals distinct tumor-promoting multicellular niches and immunosuppressive mechanisms in African American and European American patients with TNBC.
  21. Recent advances in patient-derived tumor organoids for reconstructing TME of head and neck cancer.
  22. Advances in molecular targeted drugs in combination with CAR-T cell therapy for hematologic malignancies.
  23. Hepatocellular carcinoma immune microenvironment and check point inhibitors-current status.
  24. Single clonal tracking on biomimetic microtextured platforms for real-time guided migration analysis of myeloid-derived suppressor cell dissemination characteristics ex vivo.
  25. Exploiting the immune system in hepatic tumor targeting: Unleashing the potential of drugs, natural products, and nanoparticles.
  26. Metabolic Modulation of Kynurenine Based on Kynureninase-Loaded Nanoparticle Depot Overcomes Tumor Immune Evasion in Cancer Immunotherapy.
  27. Small extracellular vesicle piR-hsa-30937 derived from pancreatic neuroendocrine neoplasms upregulates CD276 in macrophages to promote immune evasion.
  28. Nanomedicine Remodels Tumor Microenvironment for Solid Tumor Immunotherapy.
  29. Unlocking the power of immunotherapy: Combinatorial delivery of plasmid IL-15 and gemcitabine to synergistically remodeling the tumor microenvironment.
  1. Anim Cells Syst (Seoul). 2024 ;28(1): 123-136
    Reprogramming of tumor-associated macrophages by metabolites generated from tumor microenvironment.
    Seung Woo Kim, Chan Woo Kim, Young-Ah Moon, Hong Seok Kim.
      The tumor microenvironment comprises both tumor and non-tumor stromal cells, including tumor-associated macrophages (TAMs), endothelial cells, and carcinoma-associated fibroblasts. TAMs, major components of non-tumor stromal cells, play a crucial role in creating an immunosuppressive environment by releasing cytokines, chemokines, growth factors, and immune checkpoint proteins that inhibit T cell activity. During tumors develop, cancer cells release various mediators, including chemokines and metabolites, that recruit monocytes to infiltrate tumor tissues and subsequently induce an M2-like phenotype and tumor-promoting properties. Metabolites are often overlooked as metabolic waste or detoxification products but may contribute to TAM polarization. Furthermore, macrophages display a high degree of plasticity among immune cells in the tumor microenvironment, enabling them to either inhibit or facilitate cancer progression. Therefore, TAM-targeting has emerged as a promising strategy in tumor immunotherapy. This review provides an overview of multiple representative metabolites involved in TAM phenotypes, focusing on their role in pro-tumoral polarization of M2.
    Keywords:  Cancer; TAM; metabolites; polarization; tumor microenvironment
    DOI:  https://doi.org/10.1080/19768354.2024.2336249
  2. J Cancer Res Clin Oncol. 2024 Apr 05. 150(4): 177
    Effect of acute inflammatory reaction induced by biopsy on tumor microenvironment.
    Yuanyuan Chen, Hualian Liu, Yadong Sun.
      When it comes to the diagnosis of solid tumors, biopsy is always the gold standard. However, traumatic and inflammatory stimuli are so closely related to tumor initiation and development that the acute inflammatory response induced by biopsy can give rise to changes in the tumor microenvironment, including recruitment of immunosuppressive cells (M2 macrophages, Treg cells, Tumor-associated neutrophils) and secretion of inflammation-associated cytokines, to create immunosuppressive conditions that enable the increase of circulating tumor cells in the peripheral circulation and promote the metastatic spread of tumors after surgery. In this review, we discuss dynamic changes and inhibitory characteristics of biopsy on tumor microenvironment. By investigating its mechanism of action and summarizing the current therapeutic strategies for biopsy-induced tumor immunosuppressive microenvironment, the future of using biopsy-induced inflammation to improve the therapeutic effects and prognosis of patients is prospected.
    Keywords:  Biopsy; Immune cells; Inflammation; Tumor immunosuppressive microenvironment; Tumor immunotherapy
    DOI:  https://doi.org/10.1007/s00432-024-05704-7
  3. Ups J Med Sci. 2024 ;129
    Cellular plasticity in the breast cancer ecosystem.
    Kristian Pietras, Jonas Sjölund.
      The complex interplay between genetically diverse tumor cells and their microenvironment significantly influences cancer progression and therapeutic responses. This review highlights recent findings on cellular plasticity and heterogeneity within the breast cancer ecosystem, focusing on the roles of cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). We discuss evidence suggesting that breast cancer cells exhibit phenotypic plasticity driven by both intrinsic genetic factors and external microenvironmental cues, impacting treatment responses and disease recurrence. Moreover, single-cell RNA sequencing studies reveal diverse subtypes of CAFs and TAMs, each with distinct functional gene expression programs and spatial organization within the tumor microenvironment. Understanding the hierarchical relationships and niche cues governing cellular phenotypes offers new opportunities for targeted therapeutic interventions. By elucidating the organizational principles of the tumor ecosystem, future therapies may target phenotypic states or entire cellular niches, advancing precision medicine approaches in breast cancer treatment.
    Keywords:  Tumor microenvironment; cancer-associated fibroblasts; macrophages; tumor-initiating cells
    DOI:  https://doi.org/10.48101/ujms.v129.10629
  4. APL Bioeng. 2024 Jun;8(2): 021502
    Biophysical and biochemical aspects of immune cell-tumor microenvironment interactions.
    Shoham Benmelech, Thien Le, Maggie McKay, Jungmin Nam, Krupakar Subramaniam, Daniela Tellez, Grace Vlasak, Michael Mak.
      The tumor microenvironment (TME), composed of and influenced by a heterogeneous set of cancer cells and an extracellular matrix, plays a crucial role in cancer progression. The biophysical aspects of the TME (namely, its architecture and mechanics) regulate interactions and spatial distributions of cancer cells and immune cells. In this review, we discuss the factors of the TME-notably, the extracellular matrix, as well as tumor and stromal cells-that contribute to a pro-tumor, immunosuppressive response. We then discuss the ways in which cells of the innate and adaptive immune systems respond to tumors from both biochemical and biophysical perspectives, with increased focus on CD8+ and CD4+ T cells. Building upon this information, we turn to immune-based antitumor interventions-specifically, recent biophysical breakthroughs aimed at improving CAR-T cell therapy.
    DOI:  https://doi.org/10.1063/5.0195244
  5. Methods Cell Biol. 2024 ;pii: S0091-679X(23)00169-3. [Epub ahead of print]184 159-172
    In vitro generation of murine myeloid-derived suppressor cells from hematopoietic progenitor cells.
    Lorraine M Hernandez-Delgado, Andrea Laboy-Figueroa, Alondra Lopez-Velazquez, Carolina Flores-Ortiz, Kevin Alicea-Torres.
      One of the hallmarks of cancer is the expansion and accumulation of highly immunosuppressive myeloid cells known as myeloid-derived suppressor cells (MDSCs). To study MDSCs biology, differentiation from hematopoietic progenitor cells (HPC) is an useful tool to elucidate the biological and biochemical mechanisms associated with acquisition of immune suppressive activity and expansion in cancer. Although this is one of the protocols performed to study immune suppressive myeloid cells, differentiation of MDSCs from HPC is a method that allows to modify conditions of the supernatants used. In this protocol, we outline the process of differentiating HPCs into MDSCs in vitro using tumor explant supernatants to recapitulate the tumor microenvironment.
    Keywords:  Bone marrow cells; Hematopoietic progenitor cells; In vitro; Myeloid-derived suppressor cells; Tumor explant supernatant
    DOI:  https://doi.org/10.1016/bs.mcb.2023.10.001
  6. Front Immunol. 2024 ;15 1376962
    Extracellular vesicle-mediated communication between CD8+ cytotoxic T cells and tumor cells.
    Zeyu Huang, Xuehui Liu, Qinghao Guo, Yihang Zhou, Linlin Shi, Qingjin Cai, Shupei Tang, Qin Ouyang, Ji Zheng.
      Tumors pose a significant global public health challenge, resulting in numerous fatalities annually. CD8+ T cells play a crucial role in combating tumors; however, their effectiveness is compromised by the tumor itself and the tumor microenvironment (TME), resulting in reduced efficacy of immunotherapy. In this dynamic interplay, extracellular vesicles (EVs) have emerged as pivotal mediators, facilitating direct and indirect communication between tumors and CD8+ T cells. In this article, we provide an overview of how tumor-derived EVs directly regulate CD8+ T cell function by carrying bioactive molecules they carry internally and on their surface. Simultaneously, these EVs modulate the TME, indirectly influencing the efficiency of CD8+ T cell responses. Furthermore, EVs derived from CD8+ T cells exhibit a dual role: they promote tumor immune evasion while also enhancing antitumor activity. Finally, we briefly discuss current prevailing approaches that utilize functionalized EVs based on tumor-targeted therapy and tumor immunotherapy. These approaches aim to present novel perspectives for EV-based tumor treatment strategies, demonstrating potential for advancements in the field.
    Keywords:  CD8+ T cell; extracellular vesicles; immunity; tumor; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1376962
  7. Cancer Discov. 2024 Apr 04. 14(4): 653-657
    Tumor-Host Cometabolism Collaborates to Shape Cancer Immunity.
    Yingcheng Wu, Qiang Zou, Peng Jiang, Qiang Gao.
       SUMMARY: Nutrients are essential for supporting tumor growth and immune cell function in the tumor microenvironment, but emerging evidence reveals a paradoxical competition and collaboration between the metabolic demands of proliferating cancer cells and immune cell activation. Dietary interventions and metabolic immunoengineering offer promise to selectively modulate cancer and immune cell metabolism by targeting metabolic sensing processes rather than pathways directly, moving beyond conventional ideas and heralding an exciting new era of immunometabolism discovery and translation.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1509
  8. Angiogenesis. 2024 Apr 06.
    Navigating tumor angiogenesis: therapeutic perspectives and myeloid cell regulation mechanism.
    Fan Yang, Gloria Lee, Yi Fan.
      Sustained angiogenesis stands as a hallmark of cancer. The intricate vascular tumor microenvironment fuels cancer progression and metastasis, fosters therapy resistance, and facilitates immune evasion. Therapeutic strategies targeting tumor vasculature have emerged as transformative for cancer treatment, encompassing anti-angiogenesis, vessel normalization, and endothelial reprogramming. Growing evidence suggests the dynamic regulation of tumor angiogenesis by infiltrating myeloid cells, such as macrophages, myeloid-derived suppressor cells (MDSCs), and neutrophils. Understanding these regulatory mechanisms is pivotal in paving the way for successful vasculature-targeted cancer treatments. Therapeutic interventions aimed to disrupt myeloid cell-mediated tumor angiogenesis may reshape tumor microenvironment and overcome tumor resistance to radio/chemotherapy and immunotherapy.
    Keywords:  Anti-angiogenic therapy; Endothelial reprogramming; Immunotherapy; MDSCs; Macrophages; Neutrophils; Radiochemotherapy; Therapy resistance; Tumor angiogenesis; Vessel normalization
    DOI:  https://doi.org/10.1007/s10456-024-09913-z
  9. iScience. 2024 Apr 19. 27(4): 109546
    Disruption of CD47-SIRPα signaling restores inflammatory function in tumor-associated myeloid-derived suppressor cells.
    Carlo Zimarino, William Moody, Sarah E Davidson, Hafsa Munir, Jacqueline D Shields.
      Myeloid-derived suppressor cells (MDSCs) are a heterogeneous immune population with diverse immunosuppressive functions in solid tumors. Here, we explored the role of the tumor microenvironment in regulating MDSC differentiation and immunosuppressive properties via signal-regulatory protein alpha (SIRPα)/CD47 signaling. In a murine melanoma model, we observed progressive increases in monocytic MDSCs and monocyte-derived dendritic cells that exhibited potent T cell-suppressive capabilities. These adaptations could be recapitulated in vitro by exposing hematopoietic stem cells to tumor-derived factors. Engagement of CD47 with SIRPα on myeloid cells reduced their phagocytic capability, enhanced expression of immune checkpoints, increased reactive oxygen species production, and suppressed T cell proliferation. Perturbation of SIRPα signaling restored phagocytosis and antigen presentation by MDSCs, which was accompanied by renewed T cell activity and delayed tumor growth in multiple solid cancers. These data highlight that therapeutically targeting myeloid functions in combination with immune checkpoint inhibitors could enhance anti-tumor immunity.
    Keywords:  Cancer; Cell biology; Immunology; Molecular biology; Stem cells research
    DOI:  https://doi.org/10.1016/j.isci.2024.109546
  10. Methods Cell Biol. 2024 ;pii: S0091-679X(23)00105-X. [Epub ahead of print]184 85-96
    Assessment of myeloid-derived suppressor cell differentiation ex vivo.
    Ester Blanco, David Escors, Grazyna Kochan.
      Myeloid-derived suppressor cells (MDSCs) are major promoters of progression and metastasis in cancer. MDSCs inhibit the anti-tumor immune response through multiple mechanisms. The main MDSC functions in cancer are related to the inactivation of T cells and the establishment of an immunosuppressive tumor microenvironment (TME) through the production of pro-inflammatory cytokines, among other mechanisms. MDSCs are phenotypically similar to conventional myeloid cells, so their identification is challenging. Moreover, they infiltrate the tumors in limited numbers, and their purification from within the tumors is technically difficult and makes their study a challenge. Therefore, several ex vivo differentiation methods have been established. Our differentiation method leads to MDSCs that closely model tumor-infiltrating counterparts. In this protocol, MDSCs are differentiated from bone marrow precursors by incubation in differentiation medium produced by murine tumor cell lines engineered to constitutively express granulocyte-monocyte colony stimulating factor (GM-CSF). These ex vivo-generated MDSC subsets show high fidelity compared to their natural tumor-infiltrated counterparts. Moreover, the high yields of purification from these ex vivo differentiated MDSC enable their use for validation of new treatments in high-throughput assays. In this chapter we describe the engineering of a stable cell line overexpressing GM-CSF, followed by production and collection of conditioned media supporting MDSC differentiation. Finally, we detail the isolation procedure of bone marrow cells and the specific MDSC differentiation protocol.
    Keywords:  Ex vivo-generated MDSC; Myeloid-derived suppressor cells (MDSCs); Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/bs.mcb.2023.05.005
  11. Cell Biochem Funct. 2024 Apr;42(3): e3999
    The value of intratumoral microbiota in the diagnosis and prognosis of tumors.
    Lujia Zhou, Wenjie Zhang, Shiying Fan, Daorong Wang, Dong Tang.
      Intratumoral microbiota (ITM) are microorganisms present in tumor cells. ITM participate in tumor development by affecting tumor cells directly and the tumor microenvironment (TME), indirectly. Alterations in ITM instigate changes in tumor DNA, activate oncogenic pathways, induce tumor inflammatory responses, disrupt normal immune activity, and facilitate the secretion of effectors leading to tumor progression, metastasis, or diminished therapeutic effects. ITM varies significantly in different types of cancer cells and disease states. The presence of certain ITM serves as a predictor of various disease states. Thus, ITM predicts tumorigenesis, tumor grade, treatment efficacy, and prognosis, making it a potential tumor biomarker. The present study aimed to determine the mechanisms by which ITM affects tumor development, especially through the TME; highlight the significant potential of ITM in enhancing tumor diagnosis and prognosis; and outline future directions for ITM research, with a focus on the development of innovative tumor markers.
    Keywords:  diagnosis; intratumoral microbiota; prognosis; tumor
    DOI:  https://doi.org/10.1002/cbf.3999
  12. Trends Pharmacol Sci. 2024 Apr 05. pii: S0165-6147(24)00050-6. [Epub ahead of print]
    Targeting methionine metabolism in cancer: opportunities and challenges.
    Peng Bin, Chuanlong Wang, Hangchao Zhang, Yuqi Yan, Wenkai Ren.
      Reprogramming of methionine metabolism is a conserved hallmark of tumorigenesis. Recent studies have revealed mechanisms regulating methionine metabolism within the tumor microenvironment (TME) that drive both cancer development and antitumor immunity evasion. In this review article we summarize advancements in our understanding of tumor regulation of methionine metabolism and therapies in development that target tumor methionine metabolism. We also delineate the challenges of methionine blockade therapies in cancer and discuss emerging strategies to address them.
    Keywords:  antitumor immunity; cancer; drug combination; drug resistance; methionine metabolism
    DOI:  https://doi.org/10.1016/j.tips.2024.03.002
  13. bioRxiv. 2024 Mar 13. pii: 2024.03.09.584084. [Epub ahead of print]
    Tumor microenvironment immunomodulation by nanoformulated TLR 7/8 agonist and PI3k delta inhibitor enhances therapeutic benefits of radiotherapy.
    Mostafa Yazdimamaghani, Oleg V Kolupaev, Chaemin Lim, Duhyeong Hwang, Sonia J Laurie, Charles M Perou, Alexander V Kabanov, Jonathan S Serody.
      Infiltration of immunosuppressive cells into the breast tumor microenvironment (TME) is associated with suppressed effector T cell (Teff) responses, accelerated tumor growth, and poor clinical outcomes. Previous studies from our group and others identified infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as critical contributors to immune dysfunction in the orthotopic triple-negative breast cancer (TNBC) tumor model limiting the efficacy of adoptive cellular therapy. However, approaches to target these cells specifically in the TME are currently lacking. To overcome this barrier, polymeric micelles nanoparticles (PMNPs) were used for co-delivery of small molecule drugs activating Toll-like receptors 7 and 8 (TLR7/8) and inhibiting PI3K delta. The immunomodulation of the TME by TLR7/8 agonist and PI3K inhibitor altered macrophage polarization, reduced MDSC accumulation and selectively decreased tissue-resident Tregs in the TME, while enhancing the T and B cell adaptive immune response. PMNPs significantly enhanced the anti-tumor activity of local radiation therapy (RT) in mice bearing orthotopic TNBC tumors compared to RT alone. Taken together, these data demonstrate that RT combined with a nanoformulated immunostimulant restructured the TME and has promising potential for future translation combined with RT for patients with TNBC.
    DOI:  https://doi.org/10.1101/2024.03.09.584084
  14. J Hematol Oncol. 2024 Apr 02. 17(1): 16
    Nanoparticles in tumor microenvironment remodeling and cancer immunotherapy.
    Qiang Lu, Dongquan Kou, Shenghan Lou, Milad Ashrafizadeh, Amir Reza Aref, Israel Canadas, Yu Tian, Xiaojia Niu, Yuzhuo Wang, Pedram Torabian, Lingzhi Wang, Gautam Sethi, Vinay Tergaonkar, Franklin Tay, Zhennan Yuan, Peng Han.
      Cancer immunotherapy and vaccine development have significantly improved the fight against cancers. Despite these advancements, challenges remain, particularly in the clinical delivery of immunomodulatory compounds. The tumor microenvironment (TME), comprising macrophages, fibroblasts, and immune cells, plays a crucial role in immune response modulation. Nanoparticles, engineered to reshape the TME, have shown promising results in enhancing immunotherapy by facilitating targeted delivery and immune modulation. These nanoparticles can suppress fibroblast activation, promote M1 macrophage polarization, aid dendritic cell maturation, and encourage T cell infiltration. Biomimetic nanoparticles further enhance immunotherapy by increasing the internalization of immunomodulatory agents in immune cells such as dendritic cells. Moreover, exosomes, whether naturally secreted by cells in the body or bioengineered, have been explored to regulate the TME and immune-related cells to affect cancer immunotherapy. Stimuli-responsive nanocarriers, activated by pH, redox, and light conditions, exhibit the potential to accelerate immunotherapy. The co-application of nanoparticles with immune checkpoint inhibitors is an emerging strategy to boost anti-tumor immunity. With their ability to induce long-term immunity, nanoarchitectures are promising structures in vaccine development. This review underscores the critical role of nanoparticles in overcoming current challenges and driving the advancement of cancer immunotherapy and TME modification.
    Keywords:  Bioengineered nanostructures; cancer immunotherapy; Immune evasion nanoparticles; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13045-024-01535-8
  15. Methods Cell Biol. 2024 ;pii: S0091-679X(23)00087-0. [Epub ahead of print]184 105-118
    Isolation and immunosuppressive functions of myeloid-derived suppressor cell-derived exosomes.
    Mahrima Parvin, Mohammad H Rashid, Ali S Arbab.
      Myeloid-derived suppressor cells (MDSCs) are an integral part of the tumor microenvironment (TME). MDSC's involvement in the TME starts as soon as the primary tumor starts to get its blood supply causing an immunosuppressive environment and tumor cell invasion, and then at the formation of premetastatic niche through full-blown metastasis in distal organs. All of these functions don't require physical interaction of MDSC as some of the MDSC's functions can be replicated by secreted exosomes (MDSC-derived exosomes), which can alter the microenvironment through cellular interaction by fusion with the plasma membrane and subsequent release of their cargo, consisting of proteins, soluble factors, lipids, DNAs, microRNAs (miRNAs), and RNAs. In this method paper, we explained how to isolate MDSC exosomes and how to use the exosome to observe immunosuppressive function. We also discussed how to measure the number of exosomes by nanoparticle tracking analysis. Additionally, we outlined how to measure the protein of exosomes as well as the types of protein by Bradford assay and membrane cytokine array respectively. We also provided instructions on how to utilize MDSC-derived exosomes to get knowledge about in vitro immune cell migration, scratch assay with the tumor cells, and in vivo effect of MDSC exosome along with T cell function and proliferation.
    Keywords:  Exosomes; Immunosuppressive functions; Method of separation of MDSC; Myeloid-derived suppressor cells (MDSC); T-cell functions
    DOI:  https://doi.org/10.1016/bs.mcb.2023.04.006
  16. Methods Cell Biol. 2024 ;pii: S0091-679X(23)00111-5. [Epub ahead of print]184 119-131
    Characterization of lysosomal acid lipase in Ly6G+ and CD11c+ myeloid-derived suppressor cells.
    Ting Zhao, Hong Du, Cong Yan.
      Lysosomal acid lipase (LAL) is a key enzyme in the metabolic pathway of neutral lipids, whose deficiency (LAL-D) induces the differentiation of myeloid lineage cells into myeloid-derived suppressor cells (MDSCs), which promotes tumor growth and metastasis. This protocol provides detailed procedures for assessment of various LAL biochemical and physiological activities in Ly6G+ and CD11c+ MDSCs, including isolation of Ly6G+ and CD11c+ cells from the bone marrow and blood of mice, assays of LAL-D-induced cellular metabolic and mitochondrial activities, assessment of LAL-D-induced pathogenic immunosuppressive activity and tumor stimulatory activity. Pharmacological inhibition of the LAL activity was also described in both murine myeloid cells and human white blood cells.
    Keywords:  CD11c cells; Immunosuppression; Ly6G cells; Lysosomal acid lipase; Myeloid-derived suppressor cells; Tumor growth
    DOI:  https://doi.org/10.1016/bs.mcb.2023.05.011
  17. Front Mol Biosci. 2024 ;11 1340124
    Cancer-associated fibroblasts: protagonists of the tumor microenvironment in gastric cancer.
    Ece Ozmen, Tevriz Dilan Demir, Gulnihal Ozcan.
      Enhanced knowledge of the interaction of cancer cells with their environment elucidated the critical role of tumor microenvironment in tumor progression and chemoresistance. Cancer-associated fibroblasts act as the protagonists of the tumor microenvironment, fostering the metastasis, stemness, and chemoresistance of cancer cells and attenuating the anti-cancer immune responses. Gastric cancer is one of the most aggressive cancers in the clinic, refractory to anti-cancer therapies. Growing evidence indicates that cancer-associated fibroblasts are the most prominent risk factors for a poor tumor immune microenvironment and dismal prognosis in gastric cancer. Therefore, targeting cancer-associated fibroblasts may be central to surpassing resistance to conventional chemotherapeutics, molecular-targeted agents, and immunotherapies, improving survival in gastric cancer. However, the heterogeneity in cancer-associated fibroblasts may complicate the development of cancer-associated fibroblast targeting approaches. Although single-cell sequencing studies started dissecting the heterogeneity of cancer-associated fibroblasts, the research community should still answer these questions: "What makes a cancer-associated fibroblast protumorigenic?"; "How do the intracellular signaling and the secretome of different cancer-associated fibroblast subpopulations differ from each other?"; and "Which cancer-associated fibroblast subtypes predominate specific cancer types?". Unveiling these questions can pave the way for discovering efficient cancer-associated fibroblast targeting strategies. Here, we review current knowledge and perspectives on these questions, focusing on how CAFs induce aggressiveness and therapy resistance in gastric cancer. We also review potential therapeutic approaches to prevent the development and activation of cancer-associated fibroblasts via inhibition of CAF inducers and CAF markers in cancer.
    Keywords:  cancer-associated fibroblasts; chemoresistance; gastric cancer; metastasis; stemness; tumor microenvironment
    DOI:  https://doi.org/10.3389/fmolb.2024.1340124
  18. Biomed Pharmacother. 2024 Apr 03. pii: S0753-3322(24)00416-5. [Epub ahead of print]174 116532
    Efficient combination of radiotherapy and CAR-T - A systematic review.
    Wojciech Szlasa, Aleksandra Sztuder, Agnieszka Kaczmar-Dybko, Adam Maciejczyk, Jarosław Dybko.
      Chimeric antigen receptor T (CAR-T) cell therapy, a groundbreaking immunotherapy. However, it faces formidable challenges in treating solid tumors, grappling with issues like poor trafficking, limited penetration, and insufficient persistence within the tumor microenvironment (TME). CAR-T cells are engineered to express receptors that target specific cancer antigens, enhancing their ability to recognize and eliminate cancer cells. This review paper explores the intricate interplay between CAR-T therapy and radiotherapy (RT), investigating their synergistic potential. Radiotherapy, a standard cancer treatment, involves using high doses of radiation to target and damage cancer cells, disrupting their ability to grow and divide. We highlight that RT modulates the TME, augments antigen presentation, and promotes immune cell infiltration, bolstering CAR-T cell-mediated tumor eradication. Molecular insights shed light on RT-induced alterations in tumor stroma, T cell recruitment promotion, and induction of immunogenic cell death. Noteworthy, strategies, such as combining hypofractionated radiotherapy with myeloid-derived suppressor cell blockade, underscore innovative approaches to enhance CAR-T cell therapy in solid tumors. Bridging indications for RT and CAR-T cells in hematological malignancies are discussed, emphasizing scenarios where RT strategically enhances CAR-T cell efficacy. The paper critically evaluates the RT as a bridge compared to traditional chemotherapy, highlighting timing and dosage considerations crucial for optimizing CAR-T therapy outcomes. In summary, the paper provides valuable insights into the intricate molecular mechanisms activated by RT and innovative strategies to improve CAR-T cell therapy, fostering a deeper understanding of their combined potential in cancer treatment.
    Keywords:  Abscopal effect; Bridge therapy; CAR-T cells; Radiotherapy
    DOI:  https://doi.org/10.1016/j.biopha.2024.116532
  19. Methods Cell Biol. 2024 ;pii: S0091-679X(23)00088-2. [Epub ahead of print]184 133-147
    In vitro osteoclastogenesis assessment using murine myeloid-derived suppressor cells.
    Kyu Hwan Kwack, Lixia Zhang, Keith L Kirkwood.
      The study of myeloid-derived suppressor cells (MDSCs) has been commonly reported in the context of cancer immunology. MDSCs play a key role in cancer growth and progression by inhibiting both innate and adaptive immunity. In addition to the immunosuppressive function of MDSCs in cancer, a novel function of MDSCs as osteoclast precursors has recently been attracting attention. Because monocytic-MDSCs (M-MDSCs) are derived from the same myeloid lineage as macrophages, which are osteoclast progenitors, M-MDSCs can undergo differentiation into osteoclasts, contributing to bone destruction not only in the cancer microenvironment but also in inflammatory conditions including obesity and osteoarthritis. Herein, we present details of the technique to evaluate osteoclasts in vitro, as well as specific techniques to isolate M-MDSCs and identify them. This protocol can be easily adapted to isolate M-MDSCs from most pathologic conditions for easy evaluation.
    Keywords:  Monocytic myeloid-derived suppressor cells; Myeloid-derived suppressor cells; Osteoclast; Osteoclastogenesis
    DOI:  https://doi.org/10.1016/bs.mcb.2023.04.007
  20. bioRxiv. 2024 Mar 31. pii: 2024.03.17.585428. [Epub ahead of print]
    Integrative spatial omics reveals distinct tumor-promoting multicellular niches and immunosuppressive mechanisms in African American and European American patients with TNBC.
    Qian Zhu, Akhila Balasubramanian, Jaya Ruth Asirvatham, Danthasinghe Waduge Badrajee Piyarathna, Jaspreet Kaur, Nada Mohamed, Ling Wu, Megha Chatterjee, Stacy Wang, Niloufar Pourfarrokh, Uttam Rasaily, Yitian Xu, Junjun Zheng, Deborah Jebakumar, Arundathi Rao, Shu-Hsia Chen, Yi Li, Eric Chang, Xiaoxian Li, Ritu Aneja, Xiang H-F Zhang, Arun Sreekumar.
      Racial disparities in triple-negative breast cancer (TNBC) outcomes have been reported. However, the biological mechanisms underlying these disparities remain unclear. We integrated imaging mass cytometry and spatial transcriptomics, to characterize the tumor microenvironment (TME) of African American (AA) and European American (EA) patients with TNBC. The TME in AA patients was characterized by interactions between endothelial cells, macrophages, and mesenchymal-like cells, which were associated with poor patient survival. In contrast, the EA TNBC-associated niche is enriched in T-cells and neutrophils suggestive of an exhaustion and suppression of otherwise active T cell responses. Ligand-receptor and pathway analyses of race-associated niches found AA TNBC to be immune cold and hence immunotherapy resistant tumors, and EA TNBC as inflamed tumors that evolved a distinctive immunosuppressive mechanism. Our study revealed the presence of racially distinct tumor-promoting and immunosuppressive microenvironments in AA and EA patients with TNBC, which may explain the poor clinical outcomes.
    DOI:  https://doi.org/10.1101/2024.03.17.585428
  21. J Oral Pathol Med. 2024 Apr 01.
    Recent advances in patient-derived tumor organoids for reconstructing TME of head and neck cancer.
    Lin Chen, Yinyu Chen, Liangyu Ge, Qian Zhang, Jian Meng.
       BACKGROUND: The differences between existing preclinical models and the tumor microenvironment in vivo are one of the significant challenges hindering cancer therapy development. Patient-derived tumor organoids (PDTO) can highly retain tumor heterogeneity. Thus, it provides a more reliable platform for research in tumor biology, new drug screening, and precision medicine.
    METHODS: We conducted a systematic review to summarise the characteristics of the existing preclinical models, the advantages of patient-derived tumor organoids in reconstructing the tumor microenvironment, and the latest research progress. Moreover, this study deciphers organoid culture technology in the clinical precision treatment of head and neck cancer to achieve better transformation. Studies were identified through a comprehensive search of Ovid MEDLINE (Wolters Kluwer), PubMed (National Library of Medicine), web of Science (Thomson Reuters) and, Scopus (Elsevier) databases, without publication date or language restrictions.
    RESULTS: In tumor development, the interaction between cellular and non-cellular components in the tumor microenvironment (TME) has a crucial role. Co-culture, Air-liquid interface culture, microfluidics, and decellularized matrix have depicted great potential in reconstructing the tumor microenvironment and simulating tumor genesis, development, and metastasis.
    CONCLUSION: An accurate determination of stromal cells, immune cells, and extracellular matrix can be achieved by reconstructing the head and neck cancer tumor microenvironment using the PDTO model. Moreover, the interaction between head and neck cancer cells can also play an essential role in implementing the individualized precision treatment of head and neck cancer.
    Keywords:  head and neck cancer; patient‐derived tumor organoids; precision medicine; translational medicine; tumor heterogeneity
    DOI:  https://doi.org/10.1111/jop.13532
  22. Drug Resist Updat. 2024 Mar 26. pii: S1368-7646(24)00040-2. [Epub ahead of print]74 101082
    Advances in molecular targeted drugs in combination with CAR-T cell therapy for hematologic malignancies.
    Yuxian Huang, Yinjie Qin, Yingzhi He, Dezhi Qiu, Yeqin Zheng, Jiayue Wei, Lenghe Zhang, Dong-Hua Yang, Yuhua Li.
      Molecular targeted drugs and chimeric antigen receptor (CAR) T cell therapy represent specific biological treatments that have significantly improved the efficacy of treating hematologic malignancies. However, they face challenges such as drug resistance and recurrence after treatment. Combining molecular targeted drugs and CAR-T cells could regulate immunity, improve tumor microenvironment (TME), promote cell apoptosis, and enhance sensitivity to tumor cell killing. This approach might provide a dual coordinated attack on cancer cells, effectively eliminating minimal residual disease and overcoming therapy resistance. Moreover, molecular targeted drugs can directly or indirectly enhance the anti-tumor effect of CAR-T cells by inducing tumor target antigen expression, reversing CAR-T cell exhaustion, and reducing CAR-T cell associated toxic side effects. Therefore, combining molecular targeted drugs with CAR-T cells is a promising and novel tactic for treating hematologic malignancies. In this review article, we focus on analyzing the mechanism of therapy resistance and its reversal of CAR-T cell therapy resistance, as well as the synergistic mechanism, safety, and future challenges in CAR-T cell therapy in combination with molecular targeted drugs. We aim to explore the benefits of this combination therapy for patients with hematologic malignancies and provide a rationale for subsequent clinical studies.
    Keywords:  CAR-T cell; Immune regulation; Molecular targeted drug; Resistance mechanism; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.drup.2024.101082
  23. World J Hepatol. 2024 Mar 27. 16(3): 353-365
    Hepatocellular carcinoma immune microenvironment and check point inhibitors-current status.
    Tarana Gupta, Nikhil Sai Jarpula.
      Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and has a high mortality rate. The Barcelona Clinic Liver Cancer staging system in addition to tumor staging also links the modality of treatment available to a particular stage. The recent description of the tumor microenvironment (TME) in HCC has provided a new concept of immunogenicity within the HCC. Virus-related HCC has been shown to be more immunogenic with higher expression of cytotoxic T lymphocytes and decreased elements for immunosuppression such as regulatory T cells. This immunogenic milieu provides a better response to immunotherapy especially immune checkpoint inhibitors (ICIs). In addition, the recent data on combining locoregional therapies and other strategies may convert the less immunogenic state of the TME towards higher immunogenicity. Therefore, data are emerging on the use of combinations of locoregional therapy and ICIs in unresectable or advanced HCC and has shown better survival outcomes in this difficult population.
    Keywords:  Atezolizumab; Bevacizumab; Hepatocellular carcinoma; Immune checkpoint inhibitor; Pembrolizumab; Tumor immune microenvironment
    DOI:  https://doi.org/10.4254/wjh.v16.i3.353
  24. Methods Cell Biol. 2024 ;pii: S0091-679X(24)00015-3. [Epub ahead of print]184 97-103
    Single clonal tracking on biomimetic microtextured platforms for real-time guided migration analysis of myeloid-derived suppressor cell dissemination characteristics ex vivo.
    Ana Panic, Jordan Moore, Daniel Gallego-Perez.
      Current strategies to undermine the deleterious influence of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) are lacking effective clinical solutions, in large part, due to insufficient knowledge on susceptible cellular and molecular targets. We describe here the application of biomimetic microfabricated platforms designed to analyze migratory phenotypes of MDSCs in the tumor niche ex vivo, which may enable accelerated therapeutic discovery. By mimicking the guided structural cues present in the physiological architecture of the TME, aligned microtopography substrates can elucidate potential interventions on migratory phenotypes of MDSCs at the single clonal level. Coupled with cellular and molecular biology analysis tools, our approach employs real-time tracking analysis of cell motility to probe the dissemination characteristics of MDSCs under guided migration conditions. These methods allow us to identify cellular subpopulations of interest based on their disseminative and suppressive capabilities. By doing so, we illustrate the potential of applying microscale engineering tools, in concert with dynamic live cell imaging and bioanalysis methods to uncover novel exploitable motility targets for advancing cancer therapy discovery. The inherent simplicity and extended application to a variety of contexts in tumor-associated cell migration render this method widely accessible to existing biological laboratory conditions and interests.
    Keywords:  Aligned microtopography substrates; Guided cell migration; Real time single clone tracking
    DOI:  https://doi.org/10.1016/bs.mcb.2024.01.002
  25. Pathol Res Pract. 2024 Mar 19. pii: S0344-0338(24)00177-8. [Epub ahead of print]256 155266
    Exploiting the immune system in hepatic tumor targeting: Unleashing the potential of drugs, natural products, and nanoparticles.
    Chou-Yi Hsu, Mohammed Ahmed Mustafa, Ashwani Kumar, Atreyi Pramanik, Rajiv Sharma, Faraj Mohammed, Israa Abed Jawad, Imad Jasim Mohammed, Mohammad Y Alshahrani, Noor Alhuda Mohammad Ali Khalil, Ali Turki Shnishil, Munther Kadhim Abosaoda.
      Hepatic tumors present a formidable challenge in cancer therapeutics, necessitating the exploration of novel treatment strategies. In recent years, targeting the immune system has attracted interest to augment existing therapeutic efficacy. The immune system in hepatic tumors includes numerous cells with diverse actions. CD8+ T lymphocytes, T helper 1 (Th1) CD4+ T lymphocytes, alternative M1 macrophages, and natural killer (NK) cells provide the antitumor immunity. However, Foxp3+ regulatory CD4+ T cells (Tregs), M2-like tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) are the key immune inhibitor cells. Tumor stroma can also affect these interactions. Targeting these cells and their secreted molecules is intriguing for eliminating malignant cells. The current review provides a synopsis of the immune system components involved in hepatic tumor expansion and highlights the molecular and cellular pathways that can be targeted for therapeutic intervention. It also overviews the diverse range of drugs, natural products, immunotherapy drugs, and nanoparticles that have been investigated to manipulate immune responses and bolster antitumor immunity. The review also addresses the potential advantages and challenges associated with these approaches.
    Keywords:  Immune system; Immunotherapy; Liver neoplasms; Nanoparticles; Phytochemicals
    DOI:  https://doi.org/10.1016/j.prp.2024.155266
  26. ACS Appl Mater Interfaces. 2024 Apr 04.
    Metabolic Modulation of Kynurenine Based on Kynureninase-Loaded Nanoparticle Depot Overcomes Tumor Immune Evasion in Cancer Immunotherapy.
    Se-Youl Chae, Hojeong Shin, Jiwon Woo, Seounghun Kang, Soo Min Lee, Dal-Hee Min.
      Evading recognition of immune cells is a well-known strategy of tumors used for their survival. One of the immune evasion mechanisms is the synthesis of kynurenine (KYN), a metabolite of tryptophan, which suppresses the effector T cells. Therefore, lowering the KYN concentration can be an efficient antitumor therapy by restoring the activity of immune cells. Recently, kynureninase (KYNase), which is an enzyme transforming KYN into anthranilate, was demonstrated to show the potential to decrease KYN concentration and inhibit tumor growth. However, due to the limited bioavailability and instability of proteins in vivo, it has been challenging to maintain the KYNase concentration sufficiently high in the tumor microenvironment (TME). Here, we developed a nanoparticle system loaded with KYNase, which formed a Biodegradable and Implantable Nanoparticle Depot named 'BIND' following subcutaneous injection. The BIND sustainably supplied KYNase around the TME while located around the tumor, until it eventually degraded and disappeared. As a result, the BIND system enhanced the proliferation and cytokine production of effector T cells in the TME, followed by tumor growth inhibition and increased mean survival. Finally, we showed that the BIND carrying KYNase significantly synergized with PD-1 blockade in three mouse models of colon cancer, breast cancer, and melanoma.
    Keywords:  cancer immunotherapy; drug delivery; immune evasion; kynureninase; nanomedicine
    DOI:  https://doi.org/10.1021/acsami.4c00513
  27. Cancer Immunol Res. 2024 Apr 03.
    Small extracellular vesicle piR-hsa-30937 derived from pancreatic neuroendocrine neoplasms upregulates CD276 in macrophages to promote immune evasion.
    Yuan Zhong, Ye Tian, Yan Wang, Jian'an Bai, Qin Long, Lijun Yan, Zhihui Gong, Wei Gao, Qiyun Tang.
      The role of PIWI-interacting RNAs (piRNAs) in small extracellular vesicles (sEV) derived from pancreatic neuroendocrine neoplasms (PNEN) in the tumor microenvironment (TME) remains unexplored. We used multiplex immunohistochemistry (mIHC) to analyze the expression of CD68, CD276 (B7H3) and CD3 on PNEN. CD276+ tumor-associated macrophages (TAMs) were more abundant in tumor tissues than nontumor tissues and negatively correlated with T-cell infiltration. Serum sEV piRNA sequencing was performed to identify piRNAs enriched in PNEN patients. We then investigated the function and mechanism of sEV piR-hsa-30937 in the crosstalk between tumor cells and macrophages in the PNEN TME. PNEN-derived sEV piR-hsa-30937 targeted PTEN to activate the AKT pathway and drive CD276 expression. CD276+ macrophages inhibited T-cell proliferation and IFN- production. piR-hsa-30937 knockdown and anti-CD276 treatment suppressed progression and metastasis in a preclinical model of PNEN by enhancing T-cell immunity. Thus, our data show that PNEN-derived sEV piR-hsa-30937 promotes CD276 expression in macrophages through the PTEN/AKT pathway and that CD276+ TAMs suppress T-cell antitumor immunity. sEV piR-hsa-30937 and CD276 are potential therapeutic targets for immunotherapy of PNEN.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0825
  28. J Am Chem Soc. 2024 Apr 02.
    Nanomedicine Remodels Tumor Microenvironment for Solid Tumor Immunotherapy.
    Yuedong Guo, Ping Hu, Jianlin Shi.
      Although immunotherapy is relatively effective in treating hematological malignancies, their efficacy against solid tumors is still suboptimal or even noneffective presently. Compared to hematological cancers, solid tumors exhibit strikingly different immunosuppressive microenvironment, severely deteriorating the efficacy of immunotherapy: (1) chemical features such as hypoxia and mild acidity suppress the activity of immune cells, (2) the pro-tumorigenic domestication of immune cells in the microenvironment within the solid tumors further undermines the effectiveness of immunotherapy, and (3) the dense physical barrier of solid tumor tissues prevents the effective intratumoral infiltration and contact killing of active immune cells. Therefore, we believe that reversing the immunosuppressive microenvironment are of critical priority for the immunotherapy against solid tumors. Due to their unique morphologies, structures, and compositions, nanomedicines have become powerful tools for achieving this goal. In this Perspective, we will first briefly introduce the immunosuppressive microenvironment of solid tumors and then summarize the most recent progresses in nanomedicine-based immunotherapy for solid tumors by remodeling tumor immune-microenvironment in a comprehensive manner. It is highly expected that this Perspective will aid in advancing immunotherapy against solid tumors, and we are highly optimistic on the future development in this burgeoning field.
    DOI:  https://doi.org/10.1021/jacs.3c14005
  29. Int J Pharm. 2024 Mar 28. pii: S0378-5173(24)00261-8. [Epub ahead of print]655 124027
    Unlocking the power of immunotherapy: Combinatorial delivery of plasmid IL-15 and gemcitabine to synergistically remodeling the tumor microenvironment.
    Jingwen Liu, Yanyan Han, Ming Zhao, Leyuan Wang, Haiyang Hu, Dawei Chen.
      Cancer immunotherapy has emerged as a promising clinical treatment strategy in recent years. Unfortunately, the satisfactory antitumor therapeutic efficacy of immunotherapy is limited by intricate immunosuppressive tumor microenvironment (ITM). To remodel the ITM and alleviate the immune evasion, we constructed FA-PEG-modified liposomes to deliver plasmid IL-15 (pIL-15) and gemcitabine (GEM) (FPCL@pIL-15 + FPGL), respectively. The FPCL@pIL-15 (150 nm) and FPGL (120 nm) exhibited symmetrically spherical structures as well as desirable penetration and accumulation on tumor tissue depending on folic acid (FA) specialized targeting function. The transfected expression of IL-15 efficiently fosters the proliferation and co-activation of Natural killer (NK) cells and CD8+T cells through binding to IL-15R. FPGL upregulated the expression of Natural killer group 2 member D ligands (NKG2DLs) and reinforced recognition by NK cells to alleviate the immune evasion, and simultaneously promoted activation of CD8+T cells through immunogenic cell death (ICD) effects. More importantly, the combinatorial administration achieved intended anti-tumor efficacy in the subcutaneous 4T1 tumor model. In essence, we demonstrated that combining FPCL@pIL-15 with FPGL synergistically stimulates and mobilizes the immune system to reverse the ITM and trigger an anti-tumor immune response, indicating a tremendous potential for application in immunotherapy.
    Keywords:  Cancer immunotherapy; Immunogenic cell death; Immunosuppressive tumor microenvironment; NKG2D-NKG2DLs axis
    DOI:  https://doi.org/10.1016/j.ijpharm.2024.124027
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