bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023‒10‒01
23 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Role of the tumor microenvironment in the lymphatic metastasis of cervical cancer (Review).
  2. Communicator Extraordinaire: Extracellular Vesicles in the Tumor Microenvironment Are Essential Local and Long-Distance Mediators of Cancer Metastasis.
  3. An emerging research: the role of hepatocellular carcinoma-derived exosomal circRNAs in the immune microenvironment.
  4. Role of cancer-associated fibroblasts in colorectal cancer and their potential as therapeutic targets.
  5. An integrated overview of the immunosuppression features in the tumor microenvironment of pancreatic cancer.
  6. Regulatory mechanism underlying liver X receptor effects on the tumor microenvironment, inflammation and tumorigenesis.
  7. Immunomodulatory properties of the lymphatic endothelium in the tumor microenvironment.
  8. Can Exercise Enhance the Efficacy of Checkpoint Inhibition by Modulating Anti-Tumor Immunity?
  9. Metabolic adaptation of NK cell activity and behavior in tumors: challenges and therapeutic opportunities.
  10. Reprogramming of Treg cells in the inflammatory microenvironment during immunotherapy: a literature review.
  11. [Cancer-Associated Fibroblasts: Heterogeneity and Bimodality in Oncogenesis].
  12. Naive primary neutrophils play a dual role in the tumor microenvironment.
  13. Acod1 Expression in Cancer Cells Promotes Immune Evasion through the Generation of Inhibitory Peptides.
  14. Multi-Faceted Role of Cancer-Associated Adipocytes in Colorectal Cancer.
  15. The Importance of M1-and M2-Polarized Macrophages in Glioma and as Potential Treatment Targets.
  16. Beyond bacteria: How the intratumor mycobiome modulates lung adenocarcinoma progression.
  17. Cancer-associated fibroblasts in hematologic malignancies: elucidating roles and spotlighting therapeutic targets.
  18. Coculturing Liver Cancer Cells and Monocytes in Spheroids Conditions Monocytes to Adopt Tumor-associated Macrophage Phenotypes that Favor Tumor Growth via Cholesterol Metabolism.
  19. Intratumor microbiome: selective colonization in the tumor microenvironment and a vital regulator of tumor biology.
  20. Cancer-Associated Fibroblast-Induced Remodeling of Tumor Microenvironment in Recurrent Bladder Cancer.
  21. Dysregulation of DNAM-1-Mediated NK Cell Anti-Cancer Responses in the Tumor Microenvironment.
  22. Tumor metabolic crosstalk and immunotherapy.
  23. Decoding the IL-33/ST2 Axis: Its Impact on the Immune Landscape of Breast Cancer.
  1. Exp Ther Med. 2023 Oct;26(4): 486
    Role of the tumor microenvironment in the lymphatic metastasis of cervical cancer (Review).
    Lufang Wang, Shuyan Yi, Yun Teng, Wenhan Li, Jing Cai.
      Lymphatic metastasis is the primary type of cervical cancer metastasis and is associated with an extremely poor prognosis in patients. The tumor microenvironment primarily includes cancer-associated fibroblasts, tumor-associated macrophages, myeloid-derived suppressor cells, immune and inflammatory cells, and blood and lymphatic vascular networks, which can promote the establishment of lymphatic metastatic sites within immunosuppressive microenvironments or promote lymphatic metastasis by stimulating lymphangiogenesis and epithelial-mesenchymal transformation. As the most important feature of the tumor microenvironment, hypoxia plays an essential role in lymph node metastasis. In this review, the known mechanisms of hypoxia, and the involvement of stromal components and immune inflammatory cells in the tumor microenvironment of lymphatic metastasis of cervical cancer are discussed. Additionally, a summary of the clinical trials targeting the tumor microenvironment for the treatment of cervical cancer is provided, emphasizing the potential and challenges of immunotherapy.
    Keywords:  cancer-associated fibroblast; cervical cancer; lymphatic metastasis; tumor microenvironment; tumor-associated macrophage
    DOI:  https://doi.org/10.3892/etm.2023.12185
  2. Biomedicines. 2023 Sep 14. pii: 2534. [Epub ahead of print]11(9):
    Communicator Extraordinaire: Extracellular Vesicles in the Tumor Microenvironment Are Essential Local and Long-Distance Mediators of Cancer Metastasis.
    Megan I Mitchell, Olivier Loudig.
      Human tumors are increasingly being described as a complex "ecosystem", that includes many different cell types, secreted growth factors, extracellular matrix (ECM) components, and microvessels, that altogether create the tumor microenvironment (TME). Within the TME, epithelial cancer cells control the function of surrounding stromal cells and the non-cellular ECM components in an intricate orchestra of signaling networks specifically designed for cancer cells to exploit surrounding cells for their own benefit. Tumor-derived extracellular vesicles (EVs) released into the tumor microenvironment are essential mediators in the reprogramming of surrounding stromal cells, which include cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), and tumor endothelial cells (TECs), which are responsible for the promotion of neo-angiogenesis, immune cell evasion, and invasion which are essential for cancer progression. Perhaps most importantly, tumor-derived EVs play critical roles in the metastatic dissemination of tumor cells through their two-fold role in initiating cancer cell invasion and the establishment of the pre-metastatic niche, both of which are vital for tumor cell migration, homing, and colonization at secondary tumor sites. This review discusses extracellular vesicle trafficking within the tumor microenvironment and pre-metastatic niche formation, focusing on the complex role that EVs play in orchestrating cancer-to-stromal cell communication in order to promote the metastatic dissemination of cancer cells.
    Keywords:  biomarkers; cancer; cell-to-cell communication; extracellular vesicles; metastasis
    DOI:  https://doi.org/10.3390/biomedicines11092534
  3. Front Immunol. 2023 ;14 1227150
    An emerging research: the role of hepatocellular carcinoma-derived exosomal circRNAs in the immune microenvironment.
    Huang-Zhen Xu, Xin-Yi Lin, Yun-Xian Xu, Hui-Bin Xue, Shu Lin, Tian-Wen Xu.
      Hepatocellular carcinoma (HCC), the most common primary malignancy of the liver, is one of the leading causes of cancer-related death and is associated with a poor prognosis. The tumor microenvironment (TME) of HCC comprises immune, immunosuppressive, and interstitial cells with hypoxic, angiogenic, metabolic reprogramming, inflammatory, and immunosuppressive features. Exosomes are nanoscale extracellular vesicles that secrete biologically active signaling molecules such as deoxyribonucleic acid (DNA), messenger ribonucleic acid (mRNA), microribonucleic acid (miRNA), proteins, and lipids. These signaling molecules act as messengers in the tumor microenvironment, especially the tumor immunosuppressive microenvironment. Exosomal circRNAs reshape the tumor microenvironment by prompting hypoxic stress response, stimulating angiogenesis, contributing to metabolic reprogramming, facilitating inflammatory changes in the HCC cells and inducing tumor immunosuppression. The exosomes secreted by HCC cells carry circRNA into immune cells, which intervene in the activation of immune cells and promote the overexpression of immune checkpoints to regulate immune response, leading tumor cells to acquire immunosuppressive properties. Furthermore, immunosuppression is the final result of a combination of TME-related factors, including hypoxia, angiogenesis, metabolic reprogramming, and inflammation changes. In conclusion, exosomal circRNA accelerates the tumor progression by adjusting the phenotype of the tumor microenvironment and ultimately forming an immunosuppressive microenvironment. HCC-derived exosomal circRNA can affect HCC cell proliferation, invasion, metastasis, and induction of chemoresistance. Therefore, this review aimed to summarize the composition and function of these exosomes, the role that HCC-derived exosomal circRNAs play in microenvironment formation, and the interactions between exosomes and immune cells. This review outlines the role of exosomal circRNAs in the malignant phenotype of HCC and provides a preliminary exploration of the clinical utility of exosomal circRNAs.
    Keywords:  circRNAs; exosome; hepatocellular carcinoma; immune escape; microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1227150
  4. Biochem Biophys Res Commun. 2023 Sep 23. pii: S0006-291X(23)01101-4. [Epub ahead of print]681 127-135
    Role of cancer-associated fibroblasts in colorectal cancer and their potential as therapeutic targets.
    Liping Yan, Jian Zheng, Qingyu Wang, Hua Hao.
      Cancer-associated fibroblasts (CAFs) are mesenchymal cells in the tumor microenvironment (TME). CAFs are the most abundant cellular components in the TME of solid tumors. They affect the progression and course of chemotherapy and radiotherapy in various types of tumors including colorectal cancer (CRC). CAFs can promote tumor proliferation, invasion, and metastasis; protect tumor cells from immune surveillance; and resist tumor cell apoptosis caused by chemotherapy, resulting in drug resistance to chemotherapy. In recent years, researchers have become increasingly interested CAF functions and have conducted extensive research. However, compared to other types of malignancies, our understanding of the interaction between CRC cells and CAFs remains limited. Therefore, we searched the relevant literature published in the past 10 years, and reviewed the origin, biological characteristics, heterogeneity, role in the TME, and potential therapeutic targets of CAFs, to aid future research on CAFs and tumors.
    Keywords:  Cancer-associated fibroblasts; Colorectal cancer; Signaling pathways; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbrc.2023.09.065
  5. Front Immunol. 2023 ;14 1258538
    An integrated overview of the immunosuppression features in the tumor microenvironment of pancreatic cancer.
    Jinglong Guo, Siyue Wang, Qi Gao.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. It is characterized by a complex and immunosuppressive tumor microenvironment (TME), which is primarily composed of tumor cells, stromal cells, immune cells, and acellular components. The cross-interactions and -regulations among various cell types in the TME have been recognized to profoundly shape the immunosuppression features that meaningfully affect PDAC biology and treatment outcomes. In this review, we first summarize five cellular composition modules by integrating the cellular (sub)types, phenotypes, and functions in PDAC TME. Then we discuss an integrated overview of the cross-module regulations as a determinant of the immunosuppressive TME in PDAC. We also briefly highlight TME-targeted strategies that potentially improve PDAC therapy.
    Keywords:  complex tumor microenvironment; diverse cellular cross-regulations; immunosuppression features; pancreatic cancer; targeting strategy
    DOI:  https://doi.org/10.3389/fimmu.2023.1258538
  6. Expert Opin Ther Targets. 2023 Sep 27. 1-10
    Regulatory mechanism underlying liver X receptor effects on the tumor microenvironment, inflammation and tumorigenesis.
    Heng Zhang, Jing Wang, Jiang Sun, Qiang Wang, Lanfang Guo, Xiaoli Ju.
      INTRODUCTION: Liver X receptors (LXRs) have emerged as novel targets for tumor treatment. LXRs within the tumor microenvironment show the capacity to impact tumorigenesis and tumor development by regulating the infiltration of immune cells and release of cytokines to moderate inflammation.AREAS COVERED: In this review, we present a systematic description of recent progress in understanding the impact of LXRs on the tumor microenvironment and tumorigenesis. We also summarize the antitumor effects mediated by LXRs via their regulation of cytokine expression. Additionally, we discuss the limitations of LXR research in tumor studies to date.
    EXPERT OPINION: Previous studies have demonstrated abnormal LXR expression in tumor tissues, and activation of LXRs has been shown to inhibit tumorigenesis and promote apoptosis in tumor cells. However, LXRs can also affect tumorigenesis by regulating immune cell functions within the tumor immune microenvironment. By summarizing the impact of LXRs on immune cells, we provide new insights into the multifaceted nature of LXRs as antitumor targets.
    Keywords:  Liver X receptor; cancer; cytokine; immune cell; inflammation; tumor microenvironment
    DOI:  https://doi.org/10.1080/14728222.2023.2264513
  7. Front Immunol. 2023 ;14 1235812
    Immunomodulatory properties of the lymphatic endothelium in the tumor microenvironment.
    Cristina Viúdez-Pareja, Ewa Kreft, Melissa García-Caballero.
      The tumor microenvironment (TME) is an intricate complex and dynamic structure composed of various cell types, including tumor, stromal and immune cells. Within this complex network, lymphatic endothelial cells (LECs) play a crucial role in regulating immune responses and influencing tumor progression and metastatic dissemination to lymph node and distant organs. Interestingly, LECs possess unique immunomodulatory properties that can either promote or inhibit anti-tumor immune responses. In fact, tumor-associated lymphangiogenesis can facilitate tumor cell dissemination and metastasis supporting immunoevasion, but also, different molecular mechanisms involved in LEC-mediated anti-tumor immunity have been already described. In this context, the crosstalk between cancer cells, LECs and immune cells and how this communication can shape the immune landscape in the TME is gaining increased interest in recent years. In this review, we present a comprehensive and updated report about the immunomodulatory properties of the lymphatic endothelium within the TME, with special focus on primary tumors and tumor-draining lymph nodes. Furthermore, we outline emerging research investigating the potential therapeutic strategies targeting the lymphatic endothelium to enhance anti-tumor immune responses. Understanding the intricate mechanisms involved in LEC-mediated immune modulation in the TME opens up new possibilities for the development of innovative approaches to fight cancer.
    Keywords:  immune system; lymphatic endothelial cells; lymphatic vasculature; metastasis; pre-metastatic niche; tumor microenvironment; tumor-draining lymph node
    DOI:  https://doi.org/10.3389/fimmu.2023.1235812
  8. Cancers (Basel). 2023 Sep 21. pii: 4668. [Epub ahead of print]15(18):
    Can Exercise Enhance the Efficacy of Checkpoint Inhibition by Modulating Anti-Tumor Immunity?
    Christina Brummer, Tobias Pukrop, Joachim Wiskemann, Christina Bruss, Ines Ugele, Kathrin Renner.
      Immune checkpoint inhibition (ICI) has revolutionized cancer therapy. However, response to ICI is often limited to selected subsets of patients or not durable. Tumors that are non-responsive to checkpoint inhibition are characterized by low anti-tumoral immune cell infiltration and a highly immunosuppressive tumor microenvironment. Exercise is known to promote immune cell circulation and improve immunosurveillance. Results of recent studies indicate that physical activity can induce mobilization and redistribution of immune cells towards the tumor microenvironment (TME) and therefore enhance anti-tumor immunity. This suggests a favorable impact of exercise on the efficacy of ICI. Our review delivers insight into possible molecular mechanisms of the crosstalk between muscle, tumor, and immune cells. It summarizes current data on exercise-induced effects on anti-tumor immunity and ICI in mice and men. We consider preclinical and clinical study design challenges and discuss the role of cancer type, exercise frequency, intensity, time, and type (FITT) and immune sensitivity as critical factors for exercise-induced impact on cancer immunosurveillance.
    Keywords:  NK cells; PD-1; PD-L1; T cells; anti-tumor immunity; cancer; exercise; immune checkpoint inhibition (ICI); immunotherapy; physical activity (PA); tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/cancers15184668
  9. Trends Pharmacol Sci. 2023 Sep 26. pii: S0165-6147(23)00179-7. [Epub ahead of print]
    Metabolic adaptation of NK cell activity and behavior in tumors: challenges and therapeutic opportunities.
    Shambhavi Borde, Sandro Matosevic.
      The adaptation of natural killer (NK) cells to conditions in the microenvironment of tumors is deeply affected by their metabolic activity, itself a result of nutrient availability and the metabolism of the cancer cells themselves. Elevated rates of glycolysis and lipid metabolism in cancers not only lead to the accumulation of immunosuppressive byproducts but also contribute to an environment of elevated concentrations of extracellular metabolites. This results in altered NK cell bioenergetics through changes in transcriptional and translational profiles, ultimately affecting their pharmacology and impairing NK cell responses. However, understanding the metabolic processes that drive alterations in immunological signaling on NK cells remains both difficult and vastly underexplored. We discuss the varied and complex drivers of NK cell metabolism in homeostasis and the tumor microenvironment (TME), challenges associated with their targetability, and unexplored therapeutic opportunities.
    Keywords:  NK cells; cancer immunotherapy; cancer metabolism; immunometabolism; tumor bioenergetics
    DOI:  https://doi.org/10.1016/j.tips.2023.08.009
  10. Front Immunol. 2023 ;14 1268188
    Reprogramming of Treg cells in the inflammatory microenvironment during immunotherapy: a literature review.
    Xinyan Wu, Zhigang Zhou, Qiang Cao, Yuquan Chen, Junling Gong, Qi Zhang, Yi Qiang, Yanfeng Lu, Guangzhu Cao.
      Regulatory T cells (Treg), as members of CD4+ T cells, have garnered extensive attention in the research of tumor progression. Treg cells have the function of inhibiting the immune effector cells, preventing tissue damage, and suppressing inflammation. Under the stimulation of the tumor inflammatory microenvironment (IM), the reprogramming of Treg cells enhances their suppression of immune responses, ultimately promoting tumor immune escape or tumor progression. Reducing the number of Treg cells in the IM or lowering the activity of Treg cells while preventing their reprogramming, can help promote the body's anti-tumor immune responses. This review introduces a reprogramming mechanism of Treg cells in the IM; and discusses the regulation of Treg cells on tumor progression. The control of Treg cells and the response to Treg inflammatory reprogramming in tumor immunotherapy are analyzed and countermeasures are proposed. This work will provide a foundation for downregulating the immunosuppressive role of Treg in the inflammatory environment in future tumor immunotherapy.
    Keywords:  Foxp3; Tregs; cancer progression; immune evasion; immunotherapy; inflammatory microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1268188
  11. Mol Biol (Mosk). 2023 Sep-Oct;57(5):57(5): 739-770
    [Cancer-Associated Fibroblasts: Heterogeneity and Bimodality in Oncogenesis].
    N A Lunina, D R Safina, S V Kostrov.
      Cancer-associated fibroblasts (CAFs) often form a major component of the tumor microenvironment (TMA), providing conditions for cancer cells to thrive. CAFs may contribute to tumor growth, invasion, metastasis, and resistance to therapy. However, clinical trials of treatment strategies targeting CAFs have largely failed. Moreover, there is evidence that CAFs are capable of inhibiting tumor development. The review considers the current data on the functional heterogeneity of CAFs and their bimodality in tumor development and progression. Understanding the tumor-promoting and tumor-inhibiting activities of CAFs can help to develop new diagnostic and therapeutic approaches.
    Keywords:  cancer-associated fibroblasts; heterogeneity; markers; metastasis; oncogenesis; tumor microenvironment; tumor stroma
    DOI:  https://doi.org/10.31857/S0026898423050105, EDN: YVVDRL
  12. bioRxiv. 2023 Sep 15. pii: 2023.09.15.557892. [Epub ahead of print]
    Naive primary neutrophils play a dual role in the tumor microenvironment.
    Kehinde Adebayo Babatunde, Rupsa Datta, Jose M Ayuso, Anna Huttenlocher, Melissa C Skala, David J Beebe, Sheena C Kerr.
      The tumor microenvironment (TME) is characterized by a network of cancer cells, recruited immune cells and extracellular matrix (ECM) in a hypoxic micro-environment. However, the specific role of neutrophils in the TME, and their interactions with other immune cells is still not well understood. Thus, there is a need to investigate the interaction of primary neutrophils with tumor cells and the resulting effects on tumor development. Here we use both standard well plate culture and an under oil microfluidic (UOM) assay with an integrated extracellular cell matrix (ECM) bridge to elucidate how naive primary neutrophils respond to both patient derived tumor cells and tumor cell lines. Our data demonstrated that both patient derived HNSCC tumor cells and MDA-MB-231 breast cancer cells trigger cluster formation in neutrophils, and the swarm of neutrophils restricts tumor invasion through the generation of reactive oxygen species (ROS) and neutrophil extracellular trap (NETs) release within the swarm. However, we also observed that the presence of neutrophils downregulates granzyme B in NK-92 cells and the resulting NETs can obstruct NK cells from penetrating the tumor mass in vitro suggesting a dual role for neutrophils in the TME. Further, using label-free optical metabolic imaging (OMI) we observed changes in the metabolic activities of primary neutrophils during the different swarming phases when challenged with tumor cells. Finally, our data demonstrates that neutrophils in direct contact, or in close proximity, with tumor cells exhibit greater metabolic activities (lower nicotinamide adenine dinucleotide phosphate (NAD(P)H) mean lifetime) compared to non-contact neutrophils.
    DOI:  https://doi.org/10.1101/2023.09.15.557892
  13. bioRxiv. 2023 Sep 17. pii: 2023.09.14.557799. [Epub ahead of print]
    Acod1 Expression in Cancer Cells Promotes Immune Evasion through the Generation of Inhibitory Peptides.
    James H Schofield, Joseph Longo, Ryan D Sheldon, Emma Albano, Mark A Hawk, Sean Murphy, Loan Duong, Sharif Rahmy, Xin Lu, Russell G Jones, Zachary T Schafer.
      Targeting PD-1 is an important component of many immune checkpoint blockade (ICB) therapeutic approaches. However, ICB is not an efficacious strategy in a variety of cancer types, in part due to immunosuppressive metabolites in the tumor microenvironment (TME). Here, we find that αPD-1-resistant cancer cells produce abundant itaconate (ITA) due to enhanced levels of aconitate decarboxylase (Acod1). Acod1 has an important role in the resistance to αPD-1, as decreasing Acod1 levels in αPD-1 resistant cancer cells can sensitize tumors to αPD-1 therapy. Mechanistically, cancer cells with high Acod1 inhibit the proliferation of naïve CD8 + T cells through the secretion of inhibitory factors. Surprisingly, inhibition of CD8 + T cell proliferation is not dependent on secretion of ITA, but is instead a consequence of the release of small inhibitory peptides. Our study suggests that strategies to counter the activity of Acod1 in cancer cells may sensitize tumors to ICB therapy.
    DOI:  https://doi.org/10.1101/2023.09.14.557799
  14. Biomedicines. 2023 Aug 28. pii: 2401. [Epub ahead of print]11(9):
    Multi-Faceted Role of Cancer-Associated Adipocytes in Colorectal Cancer.
    Adriana Grigoraș, Cornelia Amalinei.
      Colorectal cancer (CRC) is one of the most commonly diagnosed types of cancer, especially in obese patients, and the second cause of cancer-related death worldwide. Based on these data, extensive research has been performed over the last decades to decipher the pivotal role of the tumor microenvironment (TME) and its cellular and molecular components in CRC development and progression. In this regard, substantial progress has been made in the identification of cancer-associated adipocytes' (CAAs) characteristics, considering their active role in the CCR tumor niche, by releasing a panel of metabolites, growth factors, and inflammatory adipokines, which assist the cancer cells' development. Disposed in the tumor invasion front, CAAs exhibit a fibroblastic-like phenotype and establish a bidirectional molecular dialogue with colorectal tumor cells, which leads to functional changes in both cell types and contributes to tumor progression. CAAs also modulate the antitumor immune cells' response and promote metabolic reprogramming and chemotherapeutic resistance in colon cancer cells. This review aims to report recent cumulative data regarding the molecular mechanisms of CAAs' differentiation and their activity spectrum in the TME of CRC. A better understanding of CAAs and the molecular interplay between CAAs and tumor cells will provide insights into tumor biology and may open the perspective of new therapeutic opportunities in CRC patients.
    Keywords:  cancer-associated adipocytes; colorectal cancer; therapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/biomedicines11092401
  15. Brain Sci. 2023 Aug 31. pii: 1269. [Epub ahead of print]13(9):
    The Importance of M1-and M2-Polarized Macrophages in Glioma and as Potential Treatment Targets.
    Jiangbin Ren, Bangjie Xu, Jianghao Ren, Zhichao Liu, Lingyu Cai, Xiaotian Zhang, Weijie Wang, Shaoxun Li, Luhao Jin, Lianshu Ding.
      Glioma is the most common and malignant tumor of the central nervous system. Glioblastoma (GBM) is the most aggressive glioma, with a poor prognosis and no effective treatment because of its high invasiveness, metabolic rate, and heterogeneity. The tumor microenvironment (TME) contains many tumor-associated macrophages (TAMs), which play a critical role in tumor proliferation, invasion, metastasis, and angiogenesis and indirectly promote an immunosuppressive microenvironment. TAM is divided into tumor-suppressive M1-like (classic activation of macrophages) and tumor-supportive M2-like (alternatively activated macrophages) polarized cells. TAMs exhibit an M1-like phenotype in the initial stages of tumor progression, and along with the promotion of lysing tumors and the functions of T cells and NK cells, tumor growth is suppressed, and they rapidly transform into M2-like polarized macrophages, which promote tumor progression. In this review, we discuss the mechanism by which M1- and M2-polarized macrophages promote or inhibit the growth of glioblastoma and indicate the future directions for treatment.
    Keywords:  glioblastoma; glioma; polarization; treatment; tumor-associated macrophage
    DOI:  https://doi.org/10.3390/brainsci13091269
  16. Cancer Cell. 2023 Sep 19. pii: S1535-6108(23)00317-3. [Epub ahead of print]
    Beyond bacteria: How the intratumor mycobiome modulates lung adenocarcinoma progression.
    Zahraa Rahal, Humam Kadara.
      Increasing evidence suggests that tumors harbor diverse microbiomes, adding complexity to the tumor microenvironment. In this issue of Cancer Cell, Liu et al. highlight the role of the intratumor mycobiome, specifically Aspergillus sydowii, in promoting lung adenocarcinoma progression. A. sydowii enhances the recruitment and activation of myeloid-derived suppressor cells via IL-1β signaling driven by the β-glucan-mediated Dectin-1/CARD9 pathway.
    DOI:  https://doi.org/10.1016/j.ccell.2023.09.002
  17. Front Oncol. 2023 ;13 1193978
    Cancer-associated fibroblasts in hematologic malignancies: elucidating roles and spotlighting therapeutic targets.
    Ziyang Ding, Run Shi, Weikang Hu, Lei Tian, Rong Sun, Yang Wu, Xiaoyan Zhang.
      Hematologic malignancies comprise a diverse range of blood, bone marrow, and organ-related disorders that present significant challenges due to drug resistance, relapse, and treatment failure. Cancer-associated fibroblasts (CAFs) represent a critical component of the tumor microenvironment (TME) and have recently emerged as potential therapeutic targets. In this comprehensive review, we summarize the latest findings on the roles of CAFs in various hematologic malignancies, including acute leukemia, multiple myeloma, chronic lymphocytic leukemia, myeloproliferative neoplasms, and lymphoma. We also explore their involvement in tumor progression, drug resistance, and the various signaling pathways implicated in their activation and function. While the underlying mechanisms and the existence of multiple CAF subtypes pose challenges, targeting CAFs and their associated pathways offers a promising avenue for the development of innovative treatments to improve patient outcomes in hematologic malignancies.
    Keywords:  cancer associated fibroblast (CAF); chemoresistance; crosstalk; hematologic malignancies; therapeutic target
    DOI:  https://doi.org/10.3389/fonc.2023.1193978
  18. J Leukoc Biol. 2023 Sep 23. pii: qiad114. [Epub ahead of print]
    Coculturing Liver Cancer Cells and Monocytes in Spheroids Conditions Monocytes to Adopt Tumor-associated Macrophage Phenotypes that Favor Tumor Growth via Cholesterol Metabolism.
    Pornlapat Keawvilai, Patipark Kueanjinda, Jeerameth Klomsing, Tanapat Palaga.
      Tumor-infiltrating immune cells and their crosstalk with cancer cells in the tumor microenvironment (TME) play a crucial role in shaping tumor progression and response to therapy. We utilized three-dimension (3D) liver cancer spheroids incorporating human primary monocytes to investigate the crosstalk between tumor-associated macrophages (TAMs) and Hepatocellular carcinoma (HCC) cells, HepG2 and PLC/PRF5. Using multiplexed gene expression panels, the critical pathways involved in shaping primary human monocytes to adopt TAMs phenotypes were identified. Specific inhibitor for identified pathway was used to explore its involvement in polarization of TAMs. In the cocultured spheroids comprised of the human HCC cell lines, the infiltrating monocytes resembled protumor M2-like macrophage phenotypes. Gene expression panels of the infiltrating monocytes demonstrated that the upregulated genes were enriched in the cholesterol metabolism pathway. Cholesterol metabolism-related genes were upregulated together with the nuclear receptors, PPARG and LXR. When lysosomal acid lipase (LAL), the key enzyme necessary for the hydrolysis of lipoprotein, was inhibited, infiltrating monocytes in 3D spheroid coculture showed significantly decreased M2 marker and lipid uptake receptor expression as well as increased cellular lipid content, which indicated that cholesterol metabolism was important for conditioning the TAMs. Moreover, LAL inhibition reduced the spheroid growth and invasiveness of HCC cell lines. siRNA-mediated LAL silencing in monocytes yielded similar results upon spheroid coculture. These data indicated that liver cancer cells and infiltrating monocytes participate in crosstalk via cholesterol metabolism to condition monocytes toward TAMs, which favors tumor growth and survival, thereby promoting liver cancer progression.
    Keywords:  cholesterol metabolism; liver cancer; monocytes; tumor-associated macrophages
    DOI:  https://doi.org/10.1093/jleuko/qiad114
  19. MedComm (2020). 2023 Oct;4(5): e376
    Intratumor microbiome: selective colonization in the tumor microenvironment and a vital regulator of tumor biology.
    Mingjie Jiang, Zhongyuan Yang, Juanjuan Dai, Tong Wu, Zan Jiao, Yongchao Yu, Kang Ning, Weichao Chen, Ankui Yang.
      The polymorphic microbiome has been proposed as a new hallmark of cancer. Intratumor microbiome has been revealed to play vital roles in regulating tumor initiation and progression, but the regulatory mechanisms have not been fully uncovered. In this review, we illustrated that similar to other components in the tumor microenvironment, the reside and composition of intratumor microbiome are regulated by tumor cells and the surrounding microenvironment. The intratumor hypoxic, immune suppressive, and highly permeable microenvironment may select certain microbiomes, and tumor cells may directly interact with microbiome via molecular binding or secretions. Conversely, the intratumor microbiomes plays vital roles in regulating tumor initiation and progression via regulating the mutational landscape, the function of genes in tumor cells and modulating the tumor microenvironment, including immunity, inflammation, angiogenesis, stem cell niche, etc. Moreover, intratumor microbiome is regulated by anti-cancer therapies and actively influences therapy response, which could be a therapeutic target or engineered to be a therapy weapon in the clinic. This review highlights the intratumor microbiome as a vital component in the tumor microenvironment, uncovers potential mutual regulatory mechanisms between the tumor microenvironment and intratumor microbiome, and points out the ongoing research directions and drawbacks of the research area, which should broaden our view of microbiome and enlighten further investigation directions.
    Keywords:  colonization; microbiome; mutational landscape; mutual regulation; therapy response; tumor microenvironment
    DOI:  https://doi.org/10.1002/mco2.376
  20. Adv Sci (Weinh). 2023 Sep 24. e2303230
    Cancer-Associated Fibroblast-Induced Remodeling of Tumor Microenvironment in Recurrent Bladder Cancer.
    Ting Liang, Tao Tao, Kai Wu, Lisha Liu, Wuwu Xu, Dewang Zhou, Hu Fang, Qiuxia Ding, Guixiao Huang, Song Wu.
      Bladder carcinoma (BC) recurrence is a major clinical challenge, and targeting the tumor microenvironment (TME) is a promising therapy. However, the relationship between individual TME components, particularly cancer-associated fibroblasts (CAFs), and tumor recurrence is unclear. Here, TME heterogeneity in primary and recurrent BC is investigated using single-cell RNA sequence profiling of 62 460 cells. Two cancer stem cell (CSC) subtypes are identified in recurrent BC. An inflammatory CAF subtype, ICAM1+ iCAFs, specifically associated with BC recurrence is also identified. iCAFs are found to secrete FGF2, which acts on the CD44 receptor of rCSC-M, thereby maintaining tumor stemness and epithelial-mesenchymal transition. Additionally, THBS1+ monocytes, a group of myeloid-derived suppressor cells (MDSCs), are enriched in recurrent BC and interacted with CAFs. ICAM1+ iCAFs are found to secrete CCL2, which binds to CCR2 in MDSCs. Moreover, elevated STAT3, NFKB2, VEGFA, and CTGF levels in iCAFs reshape the TME in recurrent tumors. CCL2 inhibition in an in situ BC mouse model suppressed tumor growth, decreased MDSCs and Tregs, and fostered tumor immune suppression. The study results highlight the role of iCAFs in TME cell-cell crosstalk during recurrent BC. The identification of pivotal signaling factors driving BC relapse is promising for the development of novel therapies.
    Keywords:  bladder carcinoma; cancer-associated fibroblasts; recurrence; single-cell RNA sequencing; tumor microenvironment
    DOI:  https://doi.org/10.1002/advs.202303230
  21. Cancers (Basel). 2023 Sep 18. pii: 4616. [Epub ahead of print]15(18):
    Dysregulation of DNAM-1-Mediated NK Cell Anti-Cancer Responses in the Tumor Microenvironment.
    Rossella Paolini, Rosa Molfetta.
      NK cells play a pivotal role in anti-cancer immune responses, thanks to the expression of a wide array of inhibitory and activating receptors that regulate their cytotoxicity against transformed cells while preserving healthy cells from lysis. However, NK cells exhibit severe dysfunction in the tumor microenvironment, mainly due to the reduction of activating receptors and the induction or increased expression of inhibitory checkpoint receptors. An activating receptor that plays a central role in tumor recognition is the DNAM-1 receptor. It recognizes PVR and Nectin2 adhesion molecules, which are frequently overexpressed on the surface of cancerous cells. These ligands are also able to trigger inhibitory signals via immune checkpoint receptors that are upregulated in the tumor microenvironment and can counteract DNAM-1 activation. Among them, TIGIT has recently gained significant attention, since its targeting results in improved anti-tumor immune responses. This review aims to summarize how the recognition of PVR and Nectin2 by paired co-stimulatory/inhibitory receptors regulates NK cell-mediated clearance of transformed cells. Therapeutic approaches with the potential to reverse DNAM-1 dysfunction in the tumor microenvironment will be also discussed.
    Keywords:  DNAM-1 activating receptor; DNAM-1 dysfunction; NK cell immune surveillance; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers15184616
  22. Clin Transl Oncol. 2023 Sep 23.
    Tumor metabolic crosstalk and immunotherapy.
    Yiwen Zhang, Yueli Nie, Xiyu Liu, Xitian Wan, Yuanyuan Shi, Keyong Zhang, Pan Wu, Jian He.
      Tumor cells must resist the host's immune system while maintaining growth under harsh conditions of acidity and hypoxia, which indicates that tumors are more robust than normal tissue. Immunotherapeutic agents have little effect on solid tumors, mostly because of the tumor density and the difficulty of penetrating deeply into the tissue to achieve the theoretical therapeutic effect. Various therapeutic strategies targeting the tumor microenvironment (TME) have been developed. Immunometabolic disorders play a dominant role in treatment resistance at both the TME and host levels. Understanding immunometabolic factors and their treatment potential may be a way forward for tumor immunotherapy. Here, we summarize the metabolism of substances that affect tumor progression, the crosstalk between the TME and immunosuppression, and some potential tumor-site targets. We also summarize the progress and challenges of tumor immunotherapy.
    Keywords:  Immunotherapy; Metabolic crosstalk; Tumor inflammation; Tumor metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12094-023-03304-4
  23. Int J Mol Sci. 2023 Sep 13. pii: 14026. [Epub ahead of print]24(18):
    Decoding the IL-33/ST2 Axis: Its Impact on the Immune Landscape of Breast Cancer.
    Bojan Stojanovic, Nevena Gajovic, Milena Jurisevic, Milica Dimitrijevic Stojanovic, Marina Jovanovic, Ivan Jovanovic, Bojana S Stojanovic, Bojan Milosevic.
      Interleukin-33 (IL-33) has emerged as a critical cytokine in the regulation of the immune system, showing a pivotal role in the pathogenesis of various diseases including cancer. This review emphasizes the role of the IL-33/ST2 axis in breast cancer biology, its contribution to cancer progression and metastasis, its influence on the tumor microenvironment and cancer metabolism, and its potential as a therapeutic target. The IL-33/ST2 axis has been shown to have extensive pro-tumorigenic features in breast cancer, starting from tumor tissue proliferation and differentiation to modulating both cancer cells and anti-tumor immune response. It has also been linked to the resistance of cancer cells to conventional therapeutics. However, the role of IL-33 in cancer therapy remains controversial due to the conflicting effects of IL-33 in tumorigenesis and anti-tumor response. The possibility of targeting the IL-33/ST2 axis in tumor immunotherapy, or as an adjuvant in immune checkpoint blockade therapy, is discussed.
    Keywords:  Interleukin-33; breast cancer; immunotherapy; metastasis; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms241814026
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