bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–11–24
thirty papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Platelet-activating factor: a potential therapeutic target to improve cancer immunotherapy.
  2. Unraveling the role of cancer-associated fibroblasts in B cell lymphoma.
  3. [The role of tumor-associated macrophages in the development and progression of cervical cancer].
  4. Erythroid progenitor cell modulates cancer immunity: Insights and implications.
  5. Macrophage modulation of tumor immunity.
  6. Exosome crosstalk between cancer stem cells and tumor microenvironment: cancer progression and therapeutic strategies.
  7. Crosstalk Between the Intratumoral Microbiota and the Tumor Microenvironment: New Frontiers in Solid Tumor Progression and Treatment.
  8. Editorial: Reciprocal crosstalk between the tumor microenvironment and cancer stem cells.
  9. Fungal influence on immune cells and inflammatory responses in the tumor microenvironment (Review).
  10. CD74 promotes the formation of an immunosuppressive tumor microenvironment in triple-negative breast cancer in mice by inducing the expansion of tolerogenic dendritic cells and regulatory B cells.
  11. The influence of endothelial metabolic reprogramming on the tumor microenvironment.
  12. Platelet factor 4-induced TH1-Treg polarization suppresses antitumor immunity.
  13. Interactions between tumor-associated macrophages and regulated cell death: therapeutic implications in immuno-oncology.
  14. [Research progress on the effect of tumor-associated macrophages on breast cancer and its targeted therapy].
  15. Macrophages in tumor cell migration and metastasis.
  16. Correction: Targeting IL-33 reprograms the tumor microenvironment and potentiates antitumor response to anti-PD-L1 immunotherapy.
  17. Dendrimer/Copper(II) Complex-Mediated siRNA Delivery Disrupts Lactate Metabolism to Reprogram the Local Immune Microenvironment against Tumor Growth and Metastasis.
  18. Tumor microenvironment in primary central nervous system lymphoma (PCNSL).
  19. Oxysterols in tumor immune microenvironment (TIME).
  20. Continued attention: The role of exosomal long non-coding RNAs in tumors over the past three years.
  21. Research progress of natural products targeting tumor-associated macrophages in antitumor immunity: A review.
  22. Effect of colorectal cancer stem cells on the development and metastasis of colorectal cancer.
  23. Tricomponent immunoactivating nanomedicine to downregulate PD-L1 and polarize macrophage for photodynamic immunotherapy of colorectal cancer.
  24. Tertiary lymphoid structures in colorectal cancer.
  25. Correlation of the abundance of MDSCs, Tregs, PD-1, and PD-L1 with the efficacy of chemotherapy and prognosis in gastric cancer.
  26. CAR-T cell therapy for hepatocellular carcinoma: current trends and challenges.
  27. Endothelial-to-mesenchymal transition in the tumor microenvironment: Roles of transforming growth factor-β and matrix metalloproteins.
  28. Engineering an αCD206-synNotch Receptor: Insights into the Development of Novel Synthetic Receptors.
  29. Neutrophil extracellular traps in tumor progression of gynecologic cancers.
  30. Optimizing iNKT-driven immune responses against cancer by modulating CD1d in tumor and antigen presenting cells.
  1. Mol Oncol. 2024 Nov 19.
    Platelet-activating factor: a potential therapeutic target to improve cancer immunotherapy.
    Qi Yan, Hemn Mohammadpour.
      The tumor microenvironment (TME) fosters cancer progression by supporting the differentiation and proliferation of myeloid-derived suppressor cells (MDSCs), which play a critical role in suppressing immune responses and facilitating tumor growth. Recent findings by Dahal et al. reveal that platelet-activating factor (PAF), a lipid mediator elevated in the TME, contributes to the differentiation of neutrophils into immunosuppressive neutrophils. They showed that inhibiting PAF signaling reduces MDSC-mediated immunosuppression, thereby enhancing cytotoxic T-cell activity. This approach may improve cancer immunotherapy outcomes, particularly when combined with checkpoint blockade therapies, suggesting a promising avenue for therapeutic development.
    Keywords:  MDSC; PAF; immune therapy; neutrophil; tumor microenvironment
    DOI:  https://doi.org/10.1002/1878-0261.13758
  2. Front Immunol. 2024 ;15 1451791
    Unraveling the role of cancer-associated fibroblasts in B cell lymphoma.
    Prithviraj Mukherjee, Stephen M Ansell, Patrizia Mondello.
      Recent breakthroughs in research have sparked a paradigm shift in our understanding of cancer biology, uncovering the critical role of the crosstalk between tumor cells and the immune cells of the tumor microenvironment (TME) in malignant transformation. Fibroblasts have long been viewed as ancillary participants in cancer progression, often eclipsed by the prominence given to malignant cells. Novel investigations, however, have increasingly acknowledged the essential part played by the fibroblasts and their phenotypic doppelganger cancer-associated fibroblasts (CAFs) in fostering immunosuppression and promoting tumor progression. Here we review the cell-of-origin from which CAFs derive and their altered programs compared to their normal counterpart. We will also discuss the complex interplay between CAFs and the surrounding immune cells of the TME in the context of solid tumors and B cell lymphomas, with a focus on the "reprogrammable" role of CAFs in immunosuppression, immuno-activation and immuno-avoidance, and their implications on drug resistance. Finally, we will examine the existing and plausible therapeutic approaches targeting CAFs as a strategy to enhance treatment response.
    Keywords:  cancer associate fibroblasts (CAFs); fibroblast; immune response; lymphoma; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1451791
  3. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2024 Nov;40(11): 1029-1034
    [The role of tumor-associated macrophages in the development and progression of cervical cancer].
    Siyi Mao, Zheng Fang, Yiming Xu, Kun Yang, Shuya Yang.
      Cervical cancer (CC) has been a hot topic in the field of gynecological cancer due to its high morbidity and mortality. As one of the major components, tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment (TME), differentiating into M1 and M2 phenotypes under the influence of various cytokines, with a predominance of the M2 phenotype among TAMs. Notably, the functions of these two phenotypes are almost opposite. M1 macrophages promote inflammation and inhibit tumor development, while M2 macrophages tend to suppress the immune response and promote tumor growth. Additionally, TAMs can influence tumor invasion, metastasis and immune regulation through interacting with various lymphocytes and cytokines. Numerous studies have demonstrated that TAMs can be used as prognostic markers for CC, and as therapeutic targets in clinical setting. A deeper comprehension of interactions between TAMs and CC, achieved by integrating findings and conclusions from various studies, is conducive to the discovery of new directions for research and new perspectives for clinical treatment.
  4. Biochim Biophys Acta Rev Cancer. 2024 Nov 15. pii: S0304-419X(24)00140-9. [Epub ahead of print]1879(6): 189209
    Erythroid progenitor cell modulates cancer immunity: Insights and implications.
    Wen-Tao Mo, Cong-Fa Huang, Zhi-Jun Sun.
      The emergence of immunotherapies such as immune checkpoint blockade (ICB) has markedly enhanced cancer treatment outcomes for numerous patients. Nevertheless, the effectiveness of immunotherapy demonstrates substantial variation across different cancer types and individual patients. The immunosuppressive characteristics of the tumor microenvironment (TME) play a crucial role in contributing to this variation. Typically, people focus on cells with immunosuppressive functions in the TME, such as tumor-associated macrophages (TAMs), but research on TAMs alone cannot fully explain the complex structure and composition of the TME. Recent studies have reported that tumors can induce erythroid progenitor cells (EPCs) to exert immunosuppressive functions, not only acting within the TME but also secreting artemin in the spleen to promote tumor progression. In this review, we summarize the recent research on EPCs and tumors in recent years. We elucidate the mechanisms by which EPCs exert immunosuppressive functions in tumor-bearing conditions. In this review, we further propose potential therapeutic strategies targeting EPCs and emphasize the importance of in-depth exploration of the mechanisms by which EPCs regulate tumors and the immune system, as well as the significant clinical value of developing corresponding drugs.
    Keywords:  Cancer immunity; Erythroid progenitor cell; Immunotherapy; Spleen; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189209
  5. Science. 2024 Nov 22. 386(6724): 850-851
    Macrophage modulation of tumor immunity.
    Peter Savage.
      Macrophages deliver polarizing messages to promote immune suppression in tumors.
    DOI:  https://doi.org/10.1126/science.adt5661
  6. Stem Cell Res Ther. 2024 Nov 22. 15(1): 449
    Exosome crosstalk between cancer stem cells and tumor microenvironment: cancer progression and therapeutic strategies.
    Qi Li, Guangpeng He, Yifan Yu, Xinyu Li, Xueqiang Peng, Liang Yang.
      Cancer stem cells (CSCs) represent a small yet pivotal subset of tumor cells endowed with self-renewal capabilities. These cells are intricately linked to tumor progression and are central to drug resistance, metastasis, and recurrence. The tumor microenvironment (TME) encompasses the cancer cells and their surrounding milieu, including immune and inflammatory cells, cancer-associated fibroblasts, adjacent stromal tissues, tumor vasculature, and a variety of cytokines and chemokines. Within the TME, cells such as immune and inflammatory cells, endothelial cells, adipocytes, and fibroblasts release growth factors, cytokines, chemokines, and exosomes, which can either sustain or disrupt CSCs, thereby influencing tumor progression. Conversely, CSCs can also secrete cytokines, chemokines, and exosomes, affecting various components of the TME. Exosomes, a subset of extracellular vesicles (EVs), carry a complex cargo of nucleic acids, proteins, and lipids, playing a crucial role in the communication between CSCs and the TME. This review primarily focuses on the impact of exosomes secreted by CSCs (CSC-exo) on tumor progression, including their roles in maintaining stemness, promoting angiogenesis, facilitating metastasis, inducing immune suppression, and contributing to drug resistance. Additionally, we discuss how exosomes secreted by different cells within the TME affect CSCs. Finally, we explore the potential of utilizing exosomes to mitigate the detrimental effects of CSCs or to target and eliminate them. A thorough understanding of the exosome-mediated crosstalk between CSCs and the TME could provide valuable insights for developing targeted therapies against CSCs.
    Keywords:  Cancer stem cells; Cancer treatment; Exosomes; Extracellular vesicles; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13287-024-04061-z
  7. Cancer Rep (Hoboken). 2024 Nov;7(11): e70063
    Crosstalk Between the Intratumoral Microbiota and the Tumor Microenvironment: New Frontiers in Solid Tumor Progression and Treatment.
    Qing Zhou, Lijun Zhou, Xi Chen, Qiuyan Chen, Lu Hao.
       BACKGROUND: The microbiota plays a significant role in the tumor microenvironment, and its impact on tumor development and treatment outcome cannot be overlooked. Thus, it is essential to comprehend the interactions between the microbiota and the tumor microenvironment.
    RECENT FINDINGS: With the advent of next-generation sequencing, microbiota research has advanced significantly in recent years. The interaction between the intratumoral microbiota and the tumor microenvironment is an emerging area of research that holds great promise for understanding and treating solid tumor progression. This crosstalk between the intratumoral microbiota and the tumor microenvironment is a complex process that involves a multitude of factors, including the immune system, cellular signaling pathways, and metabolic processes. The origin of the intratumoral microbiota differs between various solid tumor, and the quantity and diversity of intratumoral microbiota also fluctuate significantly within each solid tumor.
    CONCLUSION: The aim of this review is to provide a detailed summary of the intratumoral microbiota in various types of solid tumors. This will include an analysis of their origins, differences, and how they impact the progression of solid tumors. Furthermore, we will emphasize the significant potential that the intratumoral microbiota holds for the diagnosis and treatment of solid tumors.
    Keywords:  intratumoral microbiota; origins; progression; solid tumors; treatment
    DOI:  https://doi.org/10.1002/cnr2.70063
  8. Front Immunol. 2024 ;15 1505225
    Editorial: Reciprocal crosstalk between the tumor microenvironment and cancer stem cells.
    Rosanna Paciucci, Amancio Carnero, Matilde Esther LLeonart.
      
    Keywords:  cancer; cancer stem cells; immune system; microenvironment; resistance
    DOI:  https://doi.org/10.3389/fimmu.2024.1505225
  9. Oncol Lett. 2025 Jan;29(1): 50
    Fungal influence on immune cells and inflammatory responses in the tumor microenvironment (Review).
    Jinke Zhang, Yahui Feng, Dongmei Li, Dongmei Shi.
      In recent years, a growing body of research has highlighted the significant influence of the microbiota on tumor immunity within the tumor microenvironment (TME). While much attention has been given to bacteria, emerging evidence suggests that fungi also play crucial roles in tumor development. The present review aimed to consolidate the latest findings on the mechanisms governing the interactions between fungi and the immune system or TME. By elucidating these intricate mechanisms, novel insights into the modulation of tumor immunity and therapeutic strategies may be uncovered. Ultimately, a deeper understanding of the interplay between fungi and the TME holds promise for the development of innovative management strategies and targeted drugs to enhance tumor therapy efficacy.
    Keywords:  fungi; immune; tumor microenvironment
    DOI:  https://doi.org/10.3892/ol.2024.14796
  10. PLoS Biol. 2024 Nov 22. 22(11): e3002905
    CD74 promotes the formation of an immunosuppressive tumor microenvironment in triple-negative breast cancer in mice by inducing the expansion of tolerogenic dendritic cells and regulatory B cells.
    Bianca Pellegrino, Keren David, Stav Rabani, Bar Lampert, Thuy Tran, Edward Doherty, Marta Piecychna, Roberto Meza-Romero, Lin Leng, Dov Hershkovitz, Arthur A Vandenbark, Richard Bucala, Shirly Becker-Herman, Idit Shachar.
      CD74 is a cell-surface receptor for the cytokine macrophage migration inhibitory factor (MIF). MIF binding to CD74 induces a signaling cascade resulting in the release of its cytosolic intracellular domain (CD74-ICD), which regulates transcription in naïve B and chronic lymphocytic leukemia (CLL) cells. In the current study, we investigated the role of CD74 in the regulation of the immunosuppressive tumor microenvironment (TME) in triple-negative breast cancer (TNBC). TNBC is the most aggressive breast cancer subtype and is characterized by massive infiltration of immune cells to the tumor microenvironment, making this tumor a good candidate for immunotherapy. The tumor and immune cells in TNBC express high levels of CD74; however, the function of this receptor in the tumor environment has not been extensively characterized. Regulatory B cells (Bregs) and tolerogenic dendritic cells) tol-DCs (were previously shown to attenuate the antitumor immune response in TNBC. Here, we demonstrate that CD74 enhances tumor growth by inducing the expansion of tumor-infiltrating tol-DCs and Bregs. Utilizing CD74-KO mice, Cre-flox mice lacking CD74 in CD23+ mature B cells, mice lacking CD74 in the CD11c+ population, and a CD74 inhibitor (DRQ), we elucidate the mechanism by which CD74 inhibits antitumor immunity. MIF secreted from the tumor cells activates CD74 expressed on DCs. This activation induces the binding of CD74-ICD to the SP1 promotor, resulting in the up-regulation of SP1 expression. SP1 binds the IL-1β promotor, leading to the down-regulation of its transcription. The reduced levels of IL-1β lead to decreased antitumor activity by allowing expansion of the tol-DC, which induces the expansion of the Breg population, supporting the cross-talk between these 2 populations. Taken together, these results suggest that CD74+ CD11c+ DCs are the dominant cell type involved in the regulation of TNBC progression. These findings indicate that CD74 might serve as a novel therapeutic target in TNBC.
    DOI:  https://doi.org/10.1371/journal.pbio.3002905
  11. Oncogene. 2024 Nov 20.
    The influence of endothelial metabolic reprogramming on the tumor microenvironment.
    Kelby Kane, Deanna Edwards, Jin Chen.
      Endothelial cells (ECs) that line blood vessels act as gatekeepers and shape the metabolic environment of every organ system. In normal conditions, endothelial cells are relatively quiescent with organ-specific expression signatures and metabolic profiles. In cancer, ECs are metabolically reprogrammed to promote the formation of new blood vessels to fuel tumor growth and metastasis. In addition to EC's role on tumor cells, the tortuous tumor vasculature contributes to an immunosuppressive environment by limiting T lymphocyte infiltration and activity while also promoting the recruitment of other accessory pro-angiogenic immune cells. These elements aid in the metastatic spreading of cancer cells and contribute to therapeutic resistance. The concept of restoring a more stabilized vasculature in concert with cancer immunotherapy is emerging as a potential approach to overcoming barriers in cancer treatment. This review summarizes the metabolism of endothelial cells, their regulation of nutrient uptake and delivery, and their impact in shaping the tumor microenvironment and anti-tumor immunity. We highlight new therapeutic approaches that target the tumor vasculature and harness the immune response. Appreciating the integration of metabolic state and nutrient levels and the crosstalk among immune cells, tumor cells, and ECs in the TME may provide new avenues for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41388-024-03228-5
  12. Science. 2024 Nov 22. 386(6724): eadn8608
    Platelet factor 4-induced TH1-Treg polarization suppresses antitumor immunity.
    Ayumi Kuratani, Masaaki Okamoto, Kazuki Kishida, Daisuke Okuzaki, Miwa Sasai, Shimon Sakaguchi, Hisashi Arase, Masahiro Yamamoto.
      The tumor microenvironment (TME) contains a number of immune-suppressive cells such as T helper 1-polarized regulatory T cells (TH1-Treg cells). However, little is known about the mechanism behind the abundant presence of TH1-Treg cells in the TME. We demonstrate that selective depletion of arginase I (Arg1)-expressing tumor-associated macrophages (Arg1+ TAMs) inhibits tumor growth and concurrently reduces the ratio of TH1-Treg cells in the TME. Arg1+ TAMs secrete the chemokine platelet factor 4 (PF4), which reinforces interferon-γ (IFN-γ)-induced Treg cell polarization into TH1-Treg cells in a manner dependent on CXCR3 and the IFN-γ receptor. Both genetic PF4 inactivation and PF4 neutralization hinder TH1-Treg cell accumulation in the TME and reduce tumor growth. Collectively, our study highlights the importance of Arg1+ TAM-produced PF4 for high TH1-Treg cell levels in the TME to suppress antitumor immunity.
    DOI:  https://doi.org/10.1126/science.adn8608
  13. Front Oncol. 2024 ;14 1449696
    Interactions between tumor-associated macrophages and regulated cell death: therapeutic implications in immuno-oncology.
    Yifei Ge, Lixue Jiang, Chengru Yang, Qingfu Dong, Chengwu Tang, Yi Xu, Xiangyu Zhong.
      Tumor-associated macrophages (TAMs) play a pivotal role in sculpting the tumor microenvironment and influencing cancer progression, particularly through their interactions with various forms of regulated cell death (RCD), including apoptosis, pyroptosis, ferroptosis, and necroptosis. This review examines the interplay between TAMs and these RCD pathways, exploring the mechanisms through which they interact to promote tumor growth and advancement. We examine the underlying mechanisms of these intricate interactions, emphasizing their importance in cancer progression and treatment. Moreover, we present potential therapeutic strategies for targeting TAMs and manipulating RCD to enhance anti-tumor responses. These strategies encompass reprogramming TAMs, inhibiting their recruitment, and selectively eliminating them to enhance anti-tumor functions, alongside modulating RCD pathways to amplify immune responses. These insights offer a novel perspective on tumor biology and provide a foundation for the development of more efficacious cancer therapies.
    Keywords:  apoptosis; cancer therapy; ferroptosis; necroptosis; pyroptosis; regulated cell death; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fonc.2024.1449696
  14. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2024 Nov;40(11): 1035-1043
    [Research progress on the effect of tumor-associated macrophages on breast cancer and its targeted therapy].
    Juan Zhao, Junjun Chen, Yangyun Zhou, Lingyan Xu, Xiaohe Wang, Yonglong Han.
      Tumor-associated macrophages (TAMs), a crucial component of the tumor microenvironment (TME), are closely associated to the growth, invasion, metastasis, and prognosis of breast cancer. Targeting TAMs is considered to be a potential new strategy for improving the therapeutic efficacy of breast cancer. TAMs interact with breast cancer cells and influence the development and progression of various breast cancer subtypes through multiple pathways, including the secretion of proteins, cytokines, chemokines, and exosomes. Anti-breast cancer drugs targeting TAMs and emerging therapies are continually being discovered. This article explores the effects and mechanisms of TAMs in different breast cancer subtypes, examines the anti-breast cancer effects of herbal extracts and their active ingredients targeting TAMs, and introduces new technologies such as nano-agents, gene therapy, and immunocellular therapy that target TAMs. These therapeutic strategies targeting TAMs may be critical in improving the therapeutic efficacy and prognosis of breast cancer patients.
  15. Front Immunol. 2024 ;15 1494462
    Macrophages in tumor cell migration and metastasis.
    Madeline Friedman-DeLuca, George S Karagiannis, John S Condeelis, Maja H Oktay, David Entenberg.
      Tumor-associated macrophages (TAMs) are a phenotypically diverse, highly plastic population of cells in the tumor microenvironment (TME) that have long been known to promote cancer progression. In this review, we summarize TAM ontogeny and polarization, and then explore how TAMs enhance tumor cell migration through the TME, thus facilitating metastasis. We also discuss how chemotherapy and host factors including diet, obesity, and race, impact TAM phenotype and cancer progression. In brief, TAMs induce epithelial-mesenchymal transition (EMT) in tumor cells, giving them a migratory phenotype. They promote extracellular matrix (ECM) remodeling, allowing tumor cells to migrate more easily. TAMs also provide chemotactic signals that promote tumor cell directional migration towards blood vessels, and then participate in the signaling cascade at the blood vessel that allows tumor cells to intravasate and disseminate throughout the body. Furthermore, while chemotherapy can repolarize TAMs to induce an anti-tumor response, these cytotoxic drugs can also lead to macrophage-mediated tumor relapse and metastasis. Patient response to chemotherapy may be dependent on patient-specific factors such as diet, obesity, and race, as these factors have been shown to alter macrophage phenotype and affect cancer-related outcomes. More research on how chemotherapy and patient-specific factors impact TAMs and cancer progression is needed to refine treatment strategies for cancer patients.
    Keywords:  EMT; cancer; chemotherapy; macrophages; metastasis; tumor cell migration
    DOI:  https://doi.org/10.3389/fimmu.2024.1494462
  16. J Immunother Cancer. 2024 Nov 21. pii: e009236corr1. [Epub ahead of print]12(11):
    Correction: Targeting IL-33 reprograms the tumor microenvironment and potentiates antitumor response to anti-PD-L1 immunotherapy.
      
    DOI:  https://doi.org/10.1136/jitc-2024-009236corr1
  17. Biomacromolecules. 2024 Nov 21.
    Dendrimer/Copper(II) Complex-Mediated siRNA Delivery Disrupts Lactate Metabolism to Reprogram the Local Immune Microenvironment against Tumor Growth and Metastasis.
    Yue Gao, Aiyu Li, Yanying Li, Honghua Guo, Liangyu He, Kangan Li, Dzmitry Shcharbin, Xiangyang Shi, Mingwu Shen.
      Solid tumors reprogram metabolic pathways to meet their biosynthesis demands, resulting in elevated levels of metabolites in the tumor microenvironment (TME), including lactate. Excessive accumulation and active transportation of lactate within the TME drives tumor progression, metastasis, and immunosuppression. Interruption of TME lactate metabolism is expected to restore antitumor responses and sensitize tumor immunotherapy. Herein, we developed phenylboronic acid- and pyridine-modified poly(amidoamine) dendrimer/copper(II) (Cu(II)) complexes, namely, D-Cu complexes, to deliver monocarboxylate transporter 4 siRNA (siMCT4) and disrupt the tumor lactate shuttle. The D-Cu complexes are shown to have a Cu(II)-mediated chemodynamic effect and T1-weighted magnetic resonance imaging potential (r1 relaxivity = 1.19 mM-1 s-1), enabling effective siMCT4 delivery to inhibit lactate efflux within cancer cells. In combination with a CD11b immune agonist, the treatment of D-Cu/siMCT4 polyplexes in a mouse breast tumor model alleviates local TME immunosuppression, leading to excellent inhibition of both primary tumor growth and lung metastasis.
    DOI:  https://doi.org/10.1021/acs.biomac.4c01249
  18. Cancer Biol Ther. 2024 Dec 31. 25(1): 2425131
    Tumor microenvironment in primary central nervous system lymphoma (PCNSL).
    Qiqi Jin, Haoyun Jiang, Ye Han, Litian Zhang, Cuicui Li, Yurong Zhang, Ye Chai, Pengyun Zeng, Lingling Yue, Chongyang Wu.
      Primary central nervous system lymphoma (PCNSL) is one of the rare lymphomas limited to the central nervous system. With the availability of immunotherapy, the tumor microenvironment (TME) attracts much attention nowadays. However, the systematic studies on the TME of PCNSL are lacking. By reviewing the existing research, we found that the TME of PCNSL is infiltrated with abundant TAMs and TILs, among which cytotoxic T cells (CTLs) and M2-polarized macrophages are principal. However, the counts of immune cells infiltrated in the TME of PCNSL are significantly lower than systemic diffuse large B-cell lymphoma (DLBCL). In addition, PCNSL can attract the infiltration of immunosuppressive cells and the loss of HLA I/II expression, overexpress inhibitory immune checkpoints, and release immunosuppressive cytokines to form an immunosuppressive TME. The immunosuppressive effect of TME in PCNSL is significantly stronger than that in systemic DLBCL. These characteristics of TME highlight the immunosuppression of PCNSL.
    Keywords:  IL-10; MDSCs; PCNSL; PD-1/PD-L1; TAMs; TILs; TME; Tregs
    DOI:  https://doi.org/10.1080/15384047.2024.2425131
  19. J Steroid Biochem Mol Biol. 2024 Nov 16. pii: S0960-0760(24)00182-1. [Epub ahead of print]245 106634
    Oxysterols in tumor immune microenvironment (TIME).
    Yuanxin Liu, Jie Qin, Xiaorui Li, Guangzhen Wu.
      Oxysterols are compounds generated through oxidative reactions involving cholesterol and other steroid molecules. They play a crucial role in the tumor immune microenvironment by interacting with molecules such as the cell membrane receptor EBI2 and nuclear receptors like LXR and PXR. This interaction regulates immune cell signaling pathways, affecting proliferation, apoptosis, migration, and invasion in tumor-related processes. Activating these receptors alters the function and behavior of immune cells-such as macrophages, T cells, and dendritic cells-within the tumor microenvironment, thus promoting or inhibiting tumor development. Certain oxidized steroids can increase both the number and activation of infiltrating T cells, synergizing with anti-PD-1 to enhance anti-tumor efficacy. An in-depth study of the biological mechanisms of oxidized sterols will not only enhance our understanding of the complexity of the tumor immune microenvironment but may also reveal new therapeutic targets, providing innovative strategies for tumor immunotherapy.
    Keywords:  EBI2; LXR; Oxysterol; TIME; Tumor
    DOI:  https://doi.org/10.1016/j.jsbmb.2024.106634
  20. Int Immunopharmacol. 2024 Nov 21. pii: S1567-5769(24)02188-X. [Epub ahead of print]144 113666
    Continued attention: The role of exosomal long non-coding RNAs in tumors over the past three years.
    Jiarui Cao, Bo Feng, Yanchao Xv, Jiangfan Yu, Shasha Cao, Chunzheng Ma.
      This review summarizes the research on exosomal lncRNAs in tumors over the past three years. It highlights the significant roles of exosomal lncRNAs in modulating various cellular processes within the tumor microenvironment. Exosomal lncRNAs have been shown to influence the behavior of tumor cells, promoting proliferation, metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, glycolysis, and contributing to tumor growth and metabolism. Moreover, exosomal lncRNAs have been found to interact with immune cells, such as modulating the functions of macrophages and influencing the overall immune response against tumors. Fibroblasts within the tumor microenvironment are also affected by exosomal lncRNAs, which can alter the extracellular matrix (ECM) and stromal composition. Notably, these exosomal lncRNAs hold promise in the diagnosis and treatment of tumors, offering potential biomarkers and therapeutic targets for improved clinical outcomes.
    Keywords:  Drug resistance; Exosomes; Immune cells; Long non-coding RNA; Metabolism; Microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2024.113666
  21. Medicine (Baltimore). 2024 Nov 15. 103(46): e40576
    Research progress of natural products targeting tumor-associated macrophages in antitumor immunity: A review.
    Wang Chengzhi, Liu Yifan, Zhang Xiaoqing, Liu Peimin, Li Dongdong.
      As an important innate immune cell in the body, macrophages have a strong ability to phagocytic tumor cells and maintain the innate immune response. Tumor-associated macrophages play a more prominent role in regulating tumor immunity and are currently an important target of antitumor immunity. As a new type of antitumor therapy, tumor immunotherapy has great potential, combined chemotherapy, targeting and other therapeutic means can significantly enhance the antitumor therapy effect. At present, a number of natural products have been proved to have significant immunomodulatory and antitumor effects, and have become a hot field of antitumor immunity research. Studies have found that a variety of natural products, such as polysaccharides, flavonoids, saponins, lactones, and alkaloids, can induce the polarization of M1 macrophages, inhibit the polarization of M2 macrophages, and regulate the expression of immune-related cytokines by targeting specific signaling pathways to enhance the killing effect of macrophages on tumor cells and improve the tumor immune microenvironment, and finally better play the antitumor immune function. In this paper, by summarizing the research results of the specific mechanism of natural products targeting tumor-associated macrophages to exert antitumor immunity in recent years, we discussed the aspects of natural products targeting tumor-associated macrophages to enhance antitumor immunity, in order to provide a new research idea for tumor immunotherapy and further improve the effectiveness of clinical antitumor therapy.
    DOI:  https://doi.org/10.1097/MD.0000000000040576
  22. World J Gastrointest Oncol. 2024 Nov 15. 16(11): 4354-4368
    Effect of colorectal cancer stem cells on the development and metastasis of colorectal cancer.
    Run-Zhi Deng, Xin Zheng, Zhong-Lei Lu, Ming Yuan, Qi-Chang Meng, Tao Wu, Yu Tian.
      The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role - immune checkpoints - and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
    Keywords:  Colorectal cancer; Colorectal cancer stem cells; Review; Tumor immune microenvironment; Tumor metastasis
    DOI:  https://doi.org/10.4251/wjgo.v16.i11.4354
  23. Int J Pharm. 2024 Nov 17. pii: S0378-5173(24)01202-X. [Epub ahead of print]668 124968
    Tricomponent immunoactivating nanomedicine to downregulate PD-L1 and polarize macrophage for photodynamic immunotherapy of colorectal cancer.
    Renjiang Kong, Jiaqi Huang, Yeyang Wu, Ni Yan, Xin Chen, Hong Cheng.
      The unsatisfactory immunotherapeutic responses are primarily attributed to the insufficient immune recognition and the presence of an immunosuppressive tumor microenvironment (ITM). This study focuses on the development of a tricomponent immunoactivating nanomedicine called TIN that combines a photosensitizer, an inhibitor of epidermal growth factor receptor (EGFR) and a CSF-1R inhibitor to enable photodynamic immunotherapy by downregulating PD-L1 expression and repolarizing tumor-associated macrophages (TAMs). TIN is designed to facilitate the drug delivery and target specific pathways involved in tumor progression. By inhibiting the activity of EGFR and CSF-1R, TIN reduces PD-L1 expression on tumor cells and induces the TAMs polarization to M1 phenotype, restoring the immune recognition of T cells and the phagocytosis of macrophage to reshape the immunosuppressive microenvironment. Additionally, the photodynamic therapy (PDT) of TIN can greatly destroy the primary tumor and trigger immunogenic cell death (ICD). Importantly, the immune checkpoint blockade effect of TIN can enhance the immune response of PDT-induced ICD for metastatic tumor treatment. This study presents a self-assembling strategy for the development of an all-in-one nanomedicine, effectively integrating multiple therapeutic modalities to provide a comprehensive and systemic approach for tumor suppression.
    Keywords:  Immunotherapy; PD-L1; Photodynamic therapy; Self-delivery nanomedicine; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.ijpharm.2024.124968
  24. Ann Med. 2024 Dec;56(1): 2400314
    Tertiary lymphoid structures in colorectal cancer.
    Jianyu Lv, Xiuyu Zhang, Mi Zhou, Junbin Yan, Guanqun Chao, Shuo Zhang.
       BACKGROUND: Tertiary lymphoid structures (TLS) are ectopic clusters of immune cells found in non-lymphoid tissues, particularly within the tumor microenvironment (TME). These structures resemble secondary lymphoid organs and have been identified in various solid tumors, including colorectal cancer (CRC), where they are associated with favorable prognosis. The role of TLS in modulating the immune response within the TME and their impact on cancer prognosis has garnered increasing attention in recent years.
    OBJECTIVE: This review aims to summarize the current understanding of TLS in CRC, focusing on their formation, function, and potential as prognostic markers and therapeutic targets. We explore the mechanisms by which TLS influence the immune response within the TME and their correlation with clinical outcomes in CRC patients.
    METHODS: We conducted a comprehensive review of recent studies that investigated the presence and role of TLS in CRC. The review includes data from histopathological analyses, immunohistochemical studies, and clinical trials, examining the association between TLS density, composition, and CRC prognosis. Additionally, we explored emerging therapeutic strategies targeting TLS formation and function within the TME.
    RESULTS: The presence of TLS in CRC is generally associated with an improved prognosis, particularly in early-stage disease. TLS formation is driven by chronic inflammation and is characterized by the organization of B and T cell zones, high endothelial venules (HEVs), and follicular dendritic cells (FDCs). The density and maturity of TLS are linked to better patient outcomes, including reduced recurrence rates and increased survival. Furthermore, the interplay between TLS and immune checkpoint inhibitors (ICIs) suggests potential therapeutic implications for enhancing anti-tumor immunity in CRC.
    CONCLUSIONS: TLS represent a significant prognostic marker in CRC, with their presence correlating with favorable clinical outcomes. Ongoing research is required to fully understand the mechanisms by which TLS modulate the immune response within the TME and to develop effective therapies that harness their potential. The integration of TLS-focused strategies in CRC treatment could lead to improved patient management and outcomes.
    Keywords:  Tertiary lymphoid structure; colorectal cancer; immunotherapy; microenvironment; prediction
    DOI:  https://doi.org/10.1080/07853890.2024.2400314
  25. Lab Med. 2024 Nov 20. pii: lmae090. [Epub ahead of print]
    Correlation of the abundance of MDSCs, Tregs, PD-1, and PD-L1 with the efficacy of chemotherapy and prognosis in gastric cancer.
    Na Li, Yun Li, Jing Li, Shimin Tang, Hongbo Gao, Yong Li.
       OBJECTIVE: The aim of this study was to investigate the relationship between tumor microenvironment markers (myeloid-derived suppressor cells [MDSCs], regulatory T cells [Tregs], programmed cell death 1 [PD-1], and programmed death ligand 1 [PD-L1]) and chemotherapy efficacy and prognosis in advanced gastric cancer, identifying potential monitoring indicators.
    METHODS: Advanced gastric cancer patients' MDSC and Treg expression was measured by flow cytometry pre- and postchemotherapy; PD-1 and PD-L1 expression in cancer tissues was assessed by immunohistochemistry. Correlations with chemotherapy outcomes and prognosis were analyzed.
    RESULTS: Postchemotherapy reductions in MDSC and Treg levels correlated with chemotherapy efficacy (P <.01). Negative PD-1 and PD-L1 expression in cancer tissues predicted better chemotherapy responses (P <.01). Patients with lower MDSC and Treg levels and negative PD-1 and PD-L1 had significantly longer median progression-free survival (PFS) and overall survival (OS) (P <.05).
    CONCLUSION: In advanced gastric cancer, reduced peripheral blood MDSC and Treg levels postchemotherapy and negative PD-1 and PD-L1 expression in tissues are associated with improved chemotherapy efficacy and are independent prognostic factors for PFS and OS.
    Keywords:  chemotherapy; gastric cancer; myeloid-derived suppressor cells; programmed cell death 1; programmed death ligand 1; regulatory T cells
    DOI:  https://doi.org/10.1093/labmed/lmae090
  26. Front Immunol. 2024 ;15 1489649
    CAR-T cell therapy for hepatocellular carcinoma: current trends and challenges.
    Yexin Zhou, Shanshan Wei, Menghui Xu, Xinhui Wu, Wenbo Dou, Huakang Li, Zhonglin Zhang, Shuo Zhang.
      Hepatocellular carcinoma (HCC) ranks among the most prevalent cancers worldwide, highlighting the urgent need for improved diagnostic and therapeutic methodologies. The standard treatment regimen generally involves surgical intervention followed by systemic therapies; however, the median survival rates for patients remain unsatisfactory. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a pivotal advancement in cancer treatment. Both clinical and preclinical studies emphasize the notable efficacy of CAR T cells in targeting HCC. Various molecules, such as GPC3, c-Met, and NKG2D, show significant promise as potential immunotherapeutic targets in liver cancer. Despite this, employing CAR T cells to treat solid tumors like HCC poses considerable challenges within the discipline. Numerous innovations have significant potential to enhance the efficacy of CAR T-cell therapy for HCC, including improvements in T cell trafficking, strategies to counteract the immunosuppressive tumor microenvironment, and enhanced safety protocols. Ongoing efforts to discover therapeutic targets for CAR T cells highlight the need for the development of more practical manufacturing strategies for CAR-modified cells. This review synthesizes recent findings and clinical advancements in the use of CAR T-cell therapies for HCC treatment. We elucidate the therapeutic benefits of CAR T cells in HCC and identify the primary barriers to their broader application. Our analysis aims to provide a comprehensive overview of the current status and future prospects of CAR T-cell immunotherapy for HCC.
    Keywords:  antigen; chimeric antigen receptor T cell; gene therapy; hepatocellular carcinoma; immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2024.1489649
  27. Heliyon. 2024 Nov 15. 10(21): e40118
    Endothelial-to-mesenchymal transition in the tumor microenvironment: Roles of transforming growth factor-β and matrix metalloproteins.
    Fei Du, Jing Li, Xiaolin Zhong, Zhuo Zhang, Yueshui Zhao.
      Cancer is a leading cause of global morbidity and mortality. Tumor cells grow in a complex microenvironment, comprising immune cells, stromal cells, and vascular cells, collaborating to support tumor growth and facilitate metastasis. Transforming growth factor-beta (TGF-β) is a multipotent factor that can not only affect fibrosis promotion but also assume distinct roles in the early and late stages of the tumor. Matrix metalloproteinases (MMPs) primarily function to degrade the extracellular matrix, a pivotal cellular player in tumor progression. Moreover, endothelial-to-mesenchymal transition (EndMT), similar to epithelial-to-mesenchymal transition, is associated with cancer progression by promoting angiogenesis, disrupting the endothelial barrier, and leading to cancer-associated fibroblasts. Recent studies have underscored the pivotal roles of TGF-β and MMPs in EndMT. This review delves into the contributions of TGF-β and MMPs, as well as their regulatory mechanisms, within the tumor microenvironment. This collective understanding offers fresh insights into the potential for combined targeted therapies in the fight against cancer.
    Keywords:  Combination therapy; EndMT; MMPs; TGF-β; TME
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e40118
  28. ACS Synth Biol. 2024 Nov 18.
    Engineering an αCD206-synNotch Receptor: Insights into the Development of Novel Synthetic Receptors.
    Sofija Semeniuk, Bin-Zhi Qian, Elise Cachat.
      Immune cells play a pivotal role in the establishment, growth, and progression of tumors at primary and metastatic sites. Macrophages, in particular, play a critical role in suppressing immune responses and promoting an anti-inflammatory environment through both direct and indirect cell-cell interactions. However, our understanding of the mechanisms underlying such interactions is limited due to a lack of reliable tools for studying transient interactions between cancer cells and macrophages within the tumor microenvironment. Recent advances in mammalian synthetic biology have introduced a wide range of synthetic receptors that have been used in diverse biosensing applications. One such synthetic receptor is the synNotch receptor, which can be tailored to sense specific ligands displayed on the surface of target cells. With this study, we aimed at developing a novel αCD206-synNotch receptor, targeting CD206+ macrophages, a population of macrophages that play a crucial role in promoting metastatic seeding and persistent growth. Engineered in cancer cells and used in mouse metastasis models, such a tool could help monitor─and provide an understanding of─the effects that cell-cell interactions between macrophages and cancer cells have on metastasis establishment. Here, we report the development of cancer landing-pad cells for versatile applications and the engineering of αCD206-synNotch cancer cells in particular. We report the measurement of their activity and specificity, and discuss unexpected caveats regarding their in vivo applications.
    Keywords:  CD206; cross-reactivity; macrophages; metastasis; synNotch; synthetic receptor
    DOI:  https://doi.org/10.1021/acssynbio.4c00149
  29. Front Immunol. 2024 ;15 1421889
    Neutrophil extracellular traps in tumor progression of gynecologic cancers.
    Hong Chen, Ying Zhou, Yaling Tang, Jianfa Lan, Chao Lin, Qionghua Chen, Hongying Kuang.
      This article delves into the intricate interplay between tumors, particularly gynecologic malignancies, and neutrophil extracellular traps (NETs). The relationship between tumors, specifically gynecologic malignancies, and NETs is a multifaceted and pivotal area of study. Neutrophils, pivotal components of the immune system, are tasked with combating foreign invaders. NETs, intricate structures released by neutrophils, play a vital role in combating systemic infections but also play a role in non-infectious conditions such as inflammation, autoimmune diseases, and cancer. Cancer cells have the ability to attract neutrophils, creating tumor-associated neutrophils, which then stimulate the release of NETs into the tumor microenvironment. The impact of NETs within the tumor microenvironment is profound and intricate. They play a significant role in influencing cancer development and metastasis, as well as modulating tumor immune responses. Through the release of proteases and pro-inflammatory cytokines, NETs directly alter the behavior of tumor cells, increasing invasiveness and metastatic potential. Additionally, NETs can trigger epithelial-mesenchymal transition in tumor cells, a process associated with increased invasion and metastasis. The interaction between tumors and NETs is particularly critical in gynecologic malignancies such as ovarian, cervical, and endometrial cancer. Understanding the mechanisms through which NETs operate in these tumors can offer valuable insights for the development of targeted therapeutic interventions. Researchers are actively working towards harnessing this interaction to impede tumor progression and metastasis, opening up new avenues for future treatment modalities. As our understanding of the interplay between tumors and NETs deepens, it is anticipated that novel treatment strategies will emerge, potentially leading to improved outcomes for patients with gynecologic malignancies. This article provides a comprehensive overview of the latest research findings on the interaction between NETs and cancer, particularly in gynecologic tumors, serving as a valuable resource for future exploration in this field.
    Keywords:  gynecologic cancers; metastasis and recurrence; neutrophil extracellular traps; neutrophils; new treatment strategy; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1421889
  30. Clin Immunol. 2024 Nov 17. pii: S1521-6616(24)00511-4. [Epub ahead of print]269 110402
    Optimizing iNKT-driven immune responses against cancer by modulating CD1d in tumor and antigen presenting cells.
    Ritis Kumar Shyanti, Mazharul Haque, Rajesh Singh, Manoj Mishra.
      Two major antigen processing pathways represent protein Ags through major histocompatibility complexes (MHC class I and II) or lipid Ags through CD1 molecules influence the tumor immune response. Invariant Natural Killer T cells (iNKT) manage a significant role in cancer immunotherapy. CD1d, found on antigen-presenting cells (APCs), presents lipid Ags to iNKT cells. In many cancers, the number and function of iNKT cell are compromised, leading to immune evasion. Additionally impaired motility of iNKT cells may contribute to poor tumor prognosis. Emerging evidences suggest that CD1d, itself also influences cancer progression. Patient databases further highlight the importance of CD1d expression in different cancers and its correlation with patient survival outcomes. The ability of iNKT cells to activate and enhance the immune response renders them an attractive target for cancer immunotherapy. This review discusses all the possible ways of cancer immune evasion and restoration of immune responses mediated by CD1d-iNKT interactions.
    Keywords:  CD1d; Cytokines; Invariant natural killer T cells; Lipid antigens; Tumor immunity
    DOI:  https://doi.org/10.1016/j.clim.2024.110402
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