bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2023–11–12
twenty-two papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Gut microbiota and tumor-associated macrophages: potential in tumor diagnosis and treatment.
  2. Liposomal Delivery of an Immunostimulatory Cpg Induces Robust Antitumor Immunity and Long-Term Immune Memory by Reprogramming Tumor-Associated Macrophages.
  3. Ferroptosis and tumor immunity: In perspective of the major cell components in the tumor microenvironment.
  4. Methodical Manipulation of the TME in Ovarian Cancer.
  5. Small molecule inhibitors targeting regulatory T cells for cancer treatment.
  6. Targeting post-translational modifications of Foxp3: a new paradigm for regulatory T cell-specific therapy.
  7. The Streptococcus virulence protein PepO triggers anti-tumor immune responses by reprograming tumor-associated macrophages in a mouse triple negative breast cancer model.
  8. The immune cell landscape of glioblastoma patients highlights a myeloid-enriched and immune suppressed microenvironment compared to metastatic brain tumors.
  9. Structure and functions of Mer, an innate immune checkpoint.
  10. New perspectives in cancer immunotherapy: targeting IL-6 cytokine family.
  11. Collagen-I influences the post-translational regulation, binding partners and role of Annexin A2 in breast cancer progression.
  12. Targeting cholesterol metabolism in Cancer: From molecular mechanisms to therapeutic implications.
  13. Vascular normalization: reshaping the tumor microenvironment and augmenting antitumor immunity for ovarian cancer.
  14. Tumor microenvironment heterogeneity in bladder cancer identifies biologically distinct subtypes predicting prognosis and anti-PD-L1 responses.
  15. Immunosuppressive low-density neutrophils in the blood of cancer patients display a mature phenotype.
  16. Microbiota and the landscape of the prostate tumor microenvironment.
  17. An integrated study to decipher immunosuppressive cellular communication in the PDAC environment.
  18. Melanomas and mast cells: an ambiguous relationship.
  19. Natural killer cells for pancreatic cancer immunotherapy: Role of nanoparticles.
  20. Features of the immunosuppressive tumor microenvironment in endometrial cancer based on molecular subtype.
  21. Obesity associated pancreatic ductal adenocarcinoma: Therapeutic challenges.
  22. Notch signaling regulates immunosuppressive tumor-associated macrophage function in pancreatic cancer.
  1. Gut Microbes. 2023 Dec;15(2): 2276314
    Gut microbiota and tumor-associated macrophages: potential in tumor diagnosis and treatment.
    Dongqin Zhou, Yongsheng Li.
      Avoiding immune destruction and polymorphic microbiomes are two key hallmarks of cancer. The tumor microenvironment (TME) is essential for the development of solid tumors, and the function of tumor-associated macrophages (TAMs) in the TME is closely linked to tumor prognosis. Therefore, research on TAMs could improve the progression and control of certain tumor patients. Additionally, the intestinal flora plays a crucial role in metabolizing substances and maintaining a symbiotic relationship with the host through a complex network of interactions. Recent experimental and clinical studies have suggested a potential link between gut microbiome and TME, particularly in regulating TAMs. Understanding this association could improve the efficacy of tumor immunotherapy. This review highlights the regulatory role of intestinal flora on TAMs, with a focus on gut microbiota and their metabolites. The implications of this association for tumor diagnosis and treatment are also discussed, providing a promising avenue for future clinical treatment strategies.
    Keywords:  Tumor microenvironment; cancer diagnosis; gut microbiota; immunotherapy; tumor-associated macrophages
    DOI:  https://doi.org/10.1080/19490976.2023.2276314
  2. Adv Healthc Mater. 2023 Nov 06. e2300549
    Liposomal Delivery of an Immunostimulatory Cpg Induces Robust Antitumor Immunity and Long-Term Immune Memory by Reprogramming Tumor-Associated Macrophages.
    Yujin Kim, Seojung Lee, Sangyong Jon.
      Tumor-associated macrophages (TAMs)-representative immune-suppressive cells in the tumor microenvironment (TME)-are known to promote tumor progression and metastasis, and thus have been considered an attractive target for cancer therapy. However, current TAM-targeting strategies are insufficient to result in robust antitumor efficacy. Here, we report a small lipid nanoparticle encapsulating immunostimulatory CpG oligodeoxynucleotides (SLNP@CpG) as a new immunotherapeutic modality that can reprogram TAMs and further bridge innate-to-adaptive immunity. We found that SLNP@CpG treatment enhanced macrophage-mediated phagocytosis of cancer cells and tumor antigen cross-presentation and skewed the polarization state of macrophages in vitro. Intratumoral injection of SLNP@CpG into an established murine E.G7-OVA tumor model significantly suppressed tumor growth and considerably prolonged survival, completely eradicating tumors in 83.3% of mice. Furthermore, tumor-free mice resisted rechallenge with E.G7-OVA cancer cells through induction of immunological memory and long-term antitumor immunity. SLNP@CpG even exerted antitumor efficacy in an aggressive B16-F10 melanoma model by remodeling TME towards immune stimulation and tumor elimination. These findings suggest that, by modulating the function of TAMs and reshaping an immunosuppressive TME, the SLNP@CpG nanomedicine developed here may become a promising immunotherapeutic option applicable to a variety of tumors. This article is protected by copyright. All rights reserved.
    Keywords:  CpG, liposomes; cancer immunotherapy; nanoparticles; tumor-associated macrophages
    DOI:  https://doi.org/10.1002/adhm.202300549
  3. Eur J Pharmacol. 2023 Nov 02. pii: S0014-2999(23)00638-6. [Epub ahead of print] 176124
    Ferroptosis and tumor immunity: In perspective of the major cell components in the tumor microenvironment.
    Wanling Zhu, Xiaowei Liu, Lei Yang, Qiang He, Dingming Huang, Xuelian Tan.
      Ferroptosis is an iron-dependent form of cell death driven by lipid peroxidation, which is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. Mounting studies on the essential role of ferroptosis have been published in the progression of solid tumors, metastasis, therapy, and therapy resistance. Studies showed that ferroptosis is a "double-edged sword" in tumor immunity, which means it may have both tumor-antagonizing and tumor-promoting functions. The tumor microenvironment (TME) comprises not only tumor cells but also surrounding immune cells, stromal cells, as well as noncellular components such as the extracellular matrix (ECM), cytokines, growth factors, and extracellular vesicles (EVs). In the complex and diverse condition in TME where tumor cells grow, changes in each constituent may impact tumor destiny differently. Recently, several studies have revealed the interaction between ferroptosis and different constituents in TME. Both tumor cells and nontumor cells have a dual role in tumor immunity and influence tumor progression through ferroptosis. Herein, this review aims at summarizing the role of ferroptosis in tumor immunity based on TME, focusing on the mechanisms of the interaction between the ferroptosis and the different constituents in TME, illuminating how ferroptosis plays its role in promoting or antagonizing tumors by acting with varying components in TME and proposing several questions in immunomodulatory effects of ferroptosis and ferroptosis-associated immunotherapy.
    Keywords:  Cell death; Ferroptosis; Immune cells; Tumor immunology; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ejphar.2023.176124
  4. Clin Cancer Res. 2023 Nov 08.
    Methodical Manipulation of the TME in Ovarian Cancer.
    Pamela Soberanis Pina, Amit M Oza.
      The complex interplay between ovarian cancer (OC) cells and the tumor microenvironment (TME) modulates progression, with dynamic cellular interactions influenced by external modulators, including neoadjuvant chemotherapy (NACT). A recent article described the alterations within the TME following NACT, either with or without bevacizumab, in OC.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-2365
  5. Eur J Immunol. 2023 Nov 08. e2350448
    Small molecule inhibitors targeting regulatory T cells for cancer treatment.
    Nuria García-Díaz, Qian Wei, Kjetil Taskén.
      Regulatory T cells (Tregs) are important controllers of the immune system homeostasis by preventing disproportionate immune responses. In the context of cancer, Tregs contribute to tumor development by suppressing other immune cells in the tumor microenvironment (TME). Infiltration of Tregs in the TME has been associated with poor prognosis in cancer patients. Thus, understanding the mechanisms underlying Treg recruitment and suppressive functions is essential for developing cancer immunotherapies to boost antitumor immune responses. While antibody-based strategies targeting Tregs have shown promise, small molecule inhibitors offer distinct advantages, including oral bioavailability and the ability to penetrate the TME and target intracellular proteins. Here, we provide an overview on small molecule inhibitors that have demonstrated efficacy in modulating Tregs activity in cancer and highlight the need for phenotypic assays to characterize therapeutic compounds. This article is protected by copyright. All rights reserved.
    Keywords:  Cancer; Immunotherapy; Regulatory T cells; Small molecules
    DOI:  https://doi.org/10.1002/eji.202350448
  6. Front Immunol. 2023 ;14 1280741
    Targeting post-translational modifications of Foxp3: a new paradigm for regulatory T cell-specific therapy.
    Farooq Riaz, Zhihui Huang, Fan Pan.
      A healthy immune system is pivotal for the hosts to resist external pathogens and maintain homeostasis; however, the immunosuppressive tumor microenvironment (TME) damages the anti-tumor immunity and promotes tumor progression, invasion, and metastasis. Recently, many studies have found that Foxp3+ regulatory T (Treg) cells are the major immunosuppressive cells that facilitate the formation of TME by promoting the development of various tumor-associated cells and suppressing the activity of effector immune cells. Considering the role of Tregs in tumor progression, it is pivotal to identify new therapeutic drugs to target and deplete Tregs in tumors. Although several studies have developed strategies for targeted deletion of Treg to reduce the TME and support the accumulation of effector T cells in tumors, Treg-targeted therapy systematically affects the Treg population and may lead to the progression of autoimmune diseases. It has been understood that, nevertheless, in disease conditions, Foxp3 undergoes several definite post-translational modifications (PTMs), including acetylation, glycosylation, phosphorylation, ubiquitylation, and methylation. These PTMs not only elevate or mitigate the transcriptional activity of Foxp3 but also affect the stability and immunosuppressive function of Tregs. Various studies have shown that pharmacological targeting of enzymes involved in PTMs can significantly influence the PTMs of Foxp3; thus, it may influence the progression of cancers and/or autoimmune diseases. Overall, this review will help researchers to understand the advances in the immune-suppressive mechanisms of Tregs, the post-translational regulations of Foxp3, and the potential therapeutic targets and strategies to target the Tregs in TME to improve anti-tumor immunity.
    Keywords:  Foxp3; anti-tumor immunity; autoimmune diseases; immunotherapy; post-translational modifications; regulatory T cells; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1280741
  7. Cell Biosci. 2023 Nov 04. 13(1): 198
    The Streptococcus virulence protein PepO triggers anti-tumor immune responses by reprograming tumor-associated macrophages in a mouse triple negative breast cancer model.
    Bichen Liu, Jun Huang, Jiangming Xiao, Wenlong Xu, Hong Zhang, Yuan Yuan, Yibing Yin, Xuemei Zhang.
       BACKGROUND: The efficacy of current surgery and chemotherapy for triple negative breast cancer (TNBC) is limited due to heterogenous and immunosuppressive tumor microenvironment (TME). Tumor associated macrophages (TAMs), which are regarded as an M2 tumor-promoting phenotype, are crucial in the development of the immunosuppressive TME. Targeting TAM reprograming is a promising strategy in anti-tumor therapy since reprogramming techniques provide the opportunity to actively enhance the antitumor immunological activity of TAM in addition to eliminating their tumor-supportive roles, which is rarely applied in TNBC clinically. However, how to drive M2 macrophages reprogramming into M1 with high potency remains a challenge and the molecular mechanisms how M2 macrophages polarized into M1 are poorly understood. Here, we identified a new immunoregulatory molecular PepO that was served as an immunoregulatory molecule governed the transformation of tumor-promoting M2 to tumor-inhibitory M1 cells and represented an effective anti-tumor property.
    RESULTS: At the present study, we identified a new immunoregulatory molecular PepO, as a harmless immunoregulatory molecule, governed the transformation of tumor-promoting M2 to tumor-inhibitory M1 cells efficiently. PepO-primed M2 macrophages decreased the expression of tumor-supportive molecules like Arg-1, Tgfb, Vegfa and IL-10, and increased the expression of iNOS, Cxcl9, Cxcl10, TNF-α and IL-6 to inhibit TNBC growth. Moreover, PepO enhanced the functions of macrophages related to cell killing, phagocytosis and nitric oxide biosynthetic process, thereby inhibiting the development of tumors in vivo and in vitro. Mechanistically, PepO reprogramed TAMs toward M1 by activating PI3K-AKT-mTOR pathway via TLR4 and suppressed the function of M2 by inhibiting JAK2-STAT3 pathway via TLR2. The PI3K inhibitor LY294002 abrogated the role of PepO in switching M2 macrophages into M1 and in inhibiting TNBC growth in vivo. And PepO failed to govern the M2 macrophages to reprogram into M1 macrophages and inhibit TNBC when TLR2 or TLR4 was deficient. Moreover, PepO enhanced the antitumor activity of doxorubicin and the combination exerted a synergistic effect on TNBC suppression.
    CONCLUSIONS: Our research identified a possible macrophage-based TNBC immunotherapeutic approach and suggested a novel anticancer immunoregulatory molecular called PepO.
    Keywords:  Cancer immunotherapy; Immunoregulatory molecule; Streptococcus pneumoniae endopeptidase O(PepO); Triple negative breast cancer (TNBC); Tumor associated macrophages reprograming; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13578-023-01153-w
  8. Front Immunol. 2023 ;14 1236824
    The immune cell landscape of glioblastoma patients highlights a myeloid-enriched and immune suppressed microenvironment compared to metastatic brain tumors.
    Beatrice Musca, Maria Giovanna Russo, Ada Tushe, Sara Magri, Greta Battaggia, Laura Pinton, Camilla Bonaudo, Alessandro Della Puppa, Susanna Mandruzzato.
       Introduction: Brain metastases (BrM), which commonly arise in patients with melanoma, breast cancer and lung cancer, are associated with a poor clinical prognosis. In this context, the tumor microenvironment (TME) plays an important role since it either promotes or inhibits tumor progression. Our previous studies have characterized the immunosuppressive microenvironment of glioblastoma (GBM). The aim of this study is to compare the immune profiles of BrM and GBM in order to identify potential differences that may be exploited in their differential treatment.
    Methods: Tumor and/or blood samples were taken from 20 BrM patients and 19 GBM patients. Multi-parametric flow cytometry was used to evaluate myeloid and lymphoid cells, as well as the expression of immune checkpoints in the TME and blood. In selected cases, the immunosuppressive ability of sorted myeloid cells was tested, and the ex vivo proliferation of myeloid, lymphoid and tumor cell populations was analyzed.
    Results: High frequencies of myeloid cells dominated both the BrM and GBM landscapes, but a higher presence of tumor-associated macrophages was observed in GBM, while BrM were characterized by a significant presence of tumor-infiltrating lymphocytes. Exhaustion markers were highly expressed in all T cells from both primary and metastatic brain tumors. Ex vivo analysis of the cell cycle of a single sample of a BrM and of a GBM revealed subsets of proliferating tumor cells and blood-derived macrophages, but quiescent resident microglial cells and few proliferating lymphocytes. Macrophages sorted from a single lung BrM exhibited a strong immunosuppressive activity, as previously shown for primary GBM. Finally, a significant expansion of some myeloid cell subsets was observed in the blood of both GBM and BrM patients.
    Discussion: Our results define the main characteristics of the immune profile of BrM and GBM, which are distinguished by different levels of immunosuppressive myeloid cells and lymphocytes devoid of effector function. Understanding the role of the different cells in establishing the metastatic setting is critical for improving the therapeutic efficacy of new targeted immunotherapy strategies.
    Keywords:  brain metastases; glioblastoma; myeloid cells; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2023.1236824
  9. Front Immunol. 2023 ;14 1244170
    Structure and functions of Mer, an innate immune checkpoint.
    Eric Ubil, Kashif Rafiq Zahid.
      Immunotherapy is a promising therapeutic tool that promotes the elimination of cancerous cells by a patient's own immune system. However, in the clinical setting, the number of cancer patients benefitting from immunotherapy is limited. Identification and targeting of other immune subsets, such as tumor-associated macrophages, and alternative immune checkpoints, like Mer, may further limit tumor progression and therapy resistance. In this review, we highlight the key roles of macrophage Mer signaling in immune suppression. We also summarize the role of pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes in tumor onset and progression and how Mer structure and activation can be targeted therapeutically to alter activation state. Preclinical and clinical studies focusing on Mer kinase inhibition have demonstrated the potential of targeting this innate immune checkpoint, leading to improved anti-tumor responses and patient outcomes.
    Keywords:  MerTK; MerTK inhibitors; cancer; clinical trials; immune; macrophage
    DOI:  https://doi.org/10.3389/fimmu.2023.1244170
  10. J Immunother Cancer. 2023 Nov;pii: e007530. [Epub ahead of print]11(11):
    New perspectives in cancer immunotherapy: targeting IL-6 cytokine family.
    Maria Florencia Soler, Andrea Abaurrea, Peio Azcoaga, Angela M Araujo, Maria M Caffarel.
      Chronic inflammation has been recognized as a canonical cancer hallmark. It is orchestrated by cytokines, which are master regulators of the tumor microenvironment (TME) as they represent the main communication bridge between cancer cells, the tumor stroma, and the immune system. Interleukin (IL)-6 represents a keystone cytokine in the link between inflammation and cancer. Many cytokines from the IL-6 family, which includes IL-6, oncostatin M, leukemia inhibitory factor, IL-11, IL-27, IL-31, ciliary neurotrophic factor, cardiotrophin 1, and cardiotrophin-like cytokine factor 1, have been shown to elicit tumor-promoting roles by modulating the TME, making them attractive therapeutic targets for cancer treatment.The development of immune checkpoint blockade (ICB) immunotherapies has radically changed the outcome of some cancers including melanoma, lung, and renal, although not without hurdles. However, ICB shows limited efficacy in other solid tumors. Recent reports support that chronic inflammation and IL-6 cytokine signaling are involved in resistance to immunotherapy. This review summarizes the available preclinical and clinical data regarding the implication of IL-6-related cytokines in regulating the immune TME and the response to ICB. Moreover, the potential clinical benefit of combining ICB with therapies targeting IL-6 cytokine members for cancer treatment is discussed.
    Keywords:  Cytokines; Immune Checkpoint Inhibitors; Immunotherapy; Inflammation Mediators; Tumor Microenvironment
    DOI:  https://doi.org/10.1136/jitc-2023-007530
  11. Front Oncol. 2023 ;13 1270436
    Collagen-I influences the post-translational regulation, binding partners and role of Annexin A2 in breast cancer progression.
    Amira F Mahdi, Joanne Nolan, Ruth Í O'Connor, Aoife J Lowery, Joanna M Allardyce, Patrick A Kiely, Kieran McGourty.
       Introduction: The extracellular matrix (ECM) has been heavily implicated in the development and progression of cancer. We have previously shown that Annexin A2 is integral in the migration and invasion of breast cancer cells and in the clinical progression of ER-negative breast cancer, processes which are highly influenced by the surrounding tumor microenvironment and ECM.
    Methods: We investigated how modulations of the ECM may affect the role of Annexin A2 in MDA-MB-231 breast cancer cells using western blotting, immunofluorescent confocal microscopy and immuno-precipitation mass spectrometry techniques.
    Results: We have shown that the presence of collagen-I, the main constituent of the ECM, increases the post-translational phosphorylation of Annexin A2 and subsequently causes the translocation of Annexin A2 to the extracellular surface. In the presence of collagen-I, we identified fibronectin as a novel interactor of Annexin A2, using mass spectrometry analysis. We then demonstrated that reducing Annexin A2 expression decreases the degradation of fibronectin by cancer cells and this effect on fibronectin turnover is increased according to collagen-I abundance.
    Discussion: Our results suggest that Annexin A2's role in promoting cancer progression is mediated by collagen-I and Annexin A2 maybe a therapeutic target in the bi-directional cross-talk between cancer cells and ECM remodeling that supports metastatic cancer progression.
    Keywords:  Annexin A2; breast cancer; collagen-I; extracellular matrix; metastasis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2023.1270436
  12. Biochem Pharmacol. 2023 Nov 04. pii: S0006-2952(23)00500-2. [Epub ahead of print] 115907
    Targeting cholesterol metabolism in Cancer: From molecular mechanisms to therapeutic implications.
    Jia Lu, Siwei Chen, Xuejiao Bai, Minru Liao, Yuling Qiu, Ling-Li Zheng, Haiyang Yu.
      Cholesterol is an essential component of cell membranes and helps to maintain their structure and function. Abnormal cholesterol metabolism has been linked to the development and progression of tumors. Changes in cholesterol metabolism triggered by internal or external stimuli can promote tumor growth. During metastasis, tumor cells require large amounts of cholesterol to support their growth and colonization of new organs. Recent research has shown that cholesterol metabolism is reprogrammed during tumor development, and this can also affect the anti-tumor activity of immune cells in the surrounding environment. However, identifying the specific targets in cholesterol metabolism that regulate cancer progression and the tumor microenvironment is still a challenge. Additionally, exploring the potential of combining statin drugs with other therapies for different types of cancer could be a worthwhile avenue for future drug development. In this review, we focus on the molecular mechanisms of cholesterol and its derivatives in cell metabolism and the tumor microenvironment, and discuss specific targets and relevant therapeutic agents that inhibit aspects of cholesterol homeostasis.
    Keywords:  Cancer; Cholesterol metabolism; Molecular mechanisms; Therapeutic agent; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bcp.2023.115907
  13. Front Immunol. 2023 ;14 1276694
    Vascular normalization: reshaping the tumor microenvironment and augmenting antitumor immunity for ovarian cancer.
    Ping Yu, Yaru Wang, Dahai Yuan, Yunqin Sun, Shuang Qin, Tianye Li.
      Ovarian cancer remains a challenging disease with limited treatment options and poor prognosis. The tumor microenvironment (TME) plays a crucial role in tumor growth, progression, and therapy response. One characteristic feature of the TME is the abnormal tumor vasculature, which is associated with inadequate blood perfusion, hypoxia, and immune evasion. Vascular normalization, a therapeutic strategy aiming to rectify the abnormal tumor vasculature, has emerged as a promising approach to reshape the TME, enhance antitumor immunity, and synergize with immunotherapy in ovarian cancer. This review paper provides a comprehensive overview of vascular normalization and its potential implications in ovarian cancer. In this review, we summarize the intricate interplay between anti-angiogenesis and immune modulation, as well as ICI combined with anti-angiogenesis therapy in ovarian cancer. The compelling evidence discussed in this review contributes to the growing body of knowledge supporting the utilization of combination therapy as a promising treatment paradigm for ovarian cancer, paving the way for further clinical development and optimization of this therapeutic approach.
    Keywords:  antitumor immunity; immune infiltration; immunotherapy; ovarian cancer; tumor microenvironment; vascular normalization
    DOI:  https://doi.org/10.3389/fimmu.2023.1276694
  14. Sci Rep. 2023 Nov 10. 13(1): 19563
    Tumor microenvironment heterogeneity in bladder cancer identifies biologically distinct subtypes predicting prognosis and anti-PD-L1 responses.
    YaFei Li, Yi Liu, Zhengjun Kang, Jianhua Guo, Nan Liu.
      Bladder cancer (BCa) is heterogeneous in the tumour microenvironment (TME). However, the role of the TME in BCa in modulating the response to immunotherapy has not been fully explored. We therefore analysed fractions of immune cells using CIBERSORTx and clustered BCa into subtypes. We also analyzed weighted correlation networks to generate immunotherapy-related hub genes that we used to construct a prediction model using multivariate Cox and LASSO regression analyses. We found that BCa comprised three subtypes (C1‒C3). The prognosis of the patients was the most favourable and the response rate to anti-programmed death ligand 1 (PD-L1) was the highest in C1 among the three subtypes. Immune cells, including CD8+, CD4+ memory activated, and follicular helper T cells, activated NK cells, and M1 macrophages infiltrated the C1 subtype. The C2 subtype was enriched in M0 macrophages and activated mast cells, and the C3 subtype was enriched in B and resting immune cells. Mechanistically, the enhanced immunogenicity of subtypes C1 and C2 correlated positively with a higher response rate, whereas the dysregulated ECM-related pathways in the C2 subtype and glycolytic and fatty acid metabolic pathways in the C3 subtype impaired the responses of patients to anti-PD-L1 therapy. We also constructed a TME-related signature based on 18 genes that performed well in terms of overall survival. In conclusion, we determined prognoses and anti-PD-L1 responses by analysing TME heterogeneity in BCa.
    DOI:  https://doi.org/10.1038/s41598-023-44028-3
  15. Life Sci Alliance. 2024 Jan;pii: e202302332. [Epub ahead of print]7(1):
    Immunosuppressive low-density neutrophils in the blood of cancer patients display a mature phenotype.
    Christophe Vanhaver, Frank Aboubakar Nana, Nicolas Delhez, Mathieu Luyckx, Thibault Hirsch, Alexandre Bayard, Camille Houbion, Nicolas Dauguet, Alice Brochier, Pierre van der Bruggen, Annika M Bruger.
      The presence of human neutrophils in the tumor microenvironment is strongly correlated to poor overall survival. Most previous studies have focused on the immunosuppressive capacities of low-density neutrophils (LDN), also referred to as granulocytic myeloid-derived suppressor cells, which are elevated in number in the blood of many cancer patients. We observed two types of LDN in the blood of lung cancer and ovarian carcinoma patients: CD45high LDN, which suppressed T-cell proliferation and displayed mature morphology, and CD45low LDN, which were immature and non-suppressive. We simultaneously evaluated the classical normal-density neutrophils (NDN) and, when available, tumor-associated neutrophils. We observed that NDN from cancer patients suppressed T-cell proliferation, and NDN from healthy donors did not, despite few transcriptomic differences. Hence, the immunosuppression mediated by neutrophils in the blood of cancer patients is not dependent on the cells' density but rather on their maturity.
    DOI:  https://doi.org/10.26508/lsa.202302332
  16. Am J Clin Exp Urol. 2023 ;11(5): 352-360
    Microbiota and the landscape of the prostate tumor microenvironment.
    Kasmira R Gupta, Natasha Kyprianou.
      Prostate cancer remains one of the most common causes of cancer-related death in men globally. Progression of prostate cancer to lethal metastatic disease is mediated by multiple contributors. The role of prostate microbiota and their metabolites in metastasis, therapeutic resistance to castration resistant prostate cancer (CRPC), and tumor relapse has yet to be fully investigated. Characterization of microflora can provide new mechanistic insights into the functional significance in the emergence of therapeutic resistance, identification of novel effective targeted therapies, and development of biomarkers during prostate cancer progression. The tumor microenvironment (TME) and its components work concurrently with the prostate microbiota in promoting prostate cancer development and progression to metastasis. In this article, we discuss the growing evidence on the functional contribution of microbiota to the phenotypic landscape of the TME and its effect on prostate cancer therapeutic targeting and recurrent disease.
    Keywords:  Microbiota; cell plasticity; epigenetic regulation; mesenchymal phenotype; prostate cancer; tumor microenvironment
  17. NPJ Syst Biol Appl. 2023 Nov 10. 9(1): 56
    An integrated study to decipher immunosuppressive cellular communication in the PDAC environment.
    Gülben Avşar, Pınar Pir.
      Pancreatic ductal adenocarcinoma (PDAC) is one the most aggressive cancers and characterized by a highly rigid and immunosuppressive tumor microenvironment (TME). The extensive cellular interactions are known to play key roles in the immune evasion, chemoresistance, and poor prognosis. Here, we used the spatial transcriptomics, scRNA-seq, and bulk RNA-seq datasets to enhance the insights obtained from each to decipher the cellular communication in the TME. The complex crosstalk in PDAC samples was revealed by the single-cell and spatial transcriptomics profiles of the samples. We show that tumor-associated macrophages (TAMs) are the central cell types in the regulation of microenvironment in PDAC. They colocalize with the cancer cells and tumor-suppressor immune cells and take roles to provide an immunosuppressive environment. LGALS9 gene which is upregulated in PDAC tumor samples in comparison to healthy samples was also found to be upregulated in TAMs compared to tumor-suppressor immune cells in cancer samples. Additionally, LGALS9 was found to be the primary component in the crosstalk between TAMs and the other cells. The widespread expression of P4HB gene and its interaction with LGALS9 was also notable. Our findings point to a profound role of TAMs via LGALS9 and its interaction with P4HB that should be considered for further elucidation as target in the combinatory immunotherapies for PDAC.
    DOI:  https://doi.org/10.1038/s41540-023-00320-6
  18. Melanoma Res. 2023 Nov 02.
    Melanomas and mast cells: an ambiguous relationship.
    Lisa M Kohl, Tina L Sumpter.
      Mast cells (MCs) accumulate in a broad range of tumors, including melanomas. While MCs are potent initiators of immunity in infection, and in allergic inflammation, the function of MCs in anti-melanoma immunity is unclear. MCs have the potential to release tumoricidal cytokines and proteases, to activate antigen-presenting cells and to promote anti-tumor adaptive immunity. However, within the immunosuppressive tumor microenvironment (TME), MC activation may promote angiogenesis and contribute to tumor growth. In this review, the relationship between MCs and melanomas is discussed with a focus on the impact of the TME on MC activation.
    DOI:  https://doi.org/10.1097/CMR.0000000000000932
  19. Cancer Lett. 2023 Nov 02. pii: S0304-3835(23)00413-5. [Epub ahead of print]579 216462
    Natural killer cells for pancreatic cancer immunotherapy: Role of nanoparticles.
    Virender Kumar, Ram I Mahato.
      Advanced pancreatic cancer patients have a dismal prognosis despite advances in integrative therapy. The field of tumor immunology has witnessed significant advancements for cancer treatment. However, immunotherapy for pancreatic cancer is not very effective due to its highly complex tumor microenvironment (TME). Natural killer (NK) cells are lymphocytes that play an important role in the innate immune system. NK cells do not require antigen pre-sensitization, nor are they confined by the major histocompatibility complex (MHC). NK cells have the potential to eliminate cancer cells through CAR-dependent and CAR-independent pathways, demonstrating reduced levels of systemic toxicity in the process. The availability of several potential sources of NK cells is an additional benefit that contributes to meeting the therapeutic criteria. Adding nanotechnology to enhance the functions of effector NK cells is also an appealing strategy. This article primarily discusses various approaches recently been utilized to enhance the NK functions for the treatment of pancreatic cancer. In addition, new advances in boosting NK cell therapeutic efficacy by nanoparticle mediation are presented, with a focus on pancreatic cancer.
    Keywords:  Immunotherapy; Nanoparticles; Natural killer cell; Pancreatic cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2023.216462
  20. Front Oncol. 2023 ;13 1278863
    Features of the immunosuppressive tumor microenvironment in endometrial cancer based on molecular subtype.
    Chong Zhang, Ming Wang, Yumei Wu.
      Endometrial cancer (EC) is one of the three most prevalent gynecological tumors affecting women and is the most prevalent gynecological malignancy in the developed world. Its incidence is rapidly increasing worldwide, mostly affecting postmenopausal women, whereas recently its prevalence has increased in younger people. EC is an immune gene disease and many studies have shown that the tumor-immunosuppressive microenvironment plays an important role in cancer progression. In recent years, findings regarding the immunosuppressive tumor microenvironment (ITME) of EC have included immune evasion mechanisms and immunotherapy, which are mostly immune checkpoint inhibitors (ICI) for EC. Recently studies on the ITME of different molecular types of EC have found that different molecular types may have different ITME. With the research on the immune microenvironment of EC, a new immunophenotype classification based on the immune microenvironment has been carried out in recent years. However, the impact of the ITME on EC remains unclear, and the immunophenotype of EC remains limited to the research stage. Our review describes recent findings regarding the ITME features of different EC molecular types. The advent of immunotherapy has brought hope for improved efficacy and prognosis in patients with advanced or recurrent EC. The efficacy and safety of ICIs combination therapy remains the focus of future research.
    Keywords:  endometrial cancer; immunophenotype; immunosuppressive tumor microenvironment; immunotherapy; molecular subtypes
    DOI:  https://doi.org/10.3389/fonc.2023.1278863
  21. Semin Cancer Biol. 2023 Nov 04. pii: S1044-579X(23)00135-9. [Epub ahead of print]97 12-20
    Obesity associated pancreatic ductal adenocarcinoma: Therapeutic challenges.
    Mundla Srilatha, Ramarao Malla, Megha Priya Adem, Jeremy B Foote, Ganji Purnachandra Nagaraju.
      Obesity is a prominent health issue worldwide and directly impacts pancreatic health, with obese individuals exhibiting a significant risk for increasing pancreatic ductal adenocarcinoma (PDAC). Several factors potentially explain the increased risk for the development of PDAC, including obesity-induced chronic inflammation within and outside of the pancreas, development of insulin resistance and metabolic dysfunction, promotion of immune suppression within the pancreas during inflammation, pre- and malignant stages, variations in hormones levels (adiponectin, ghrelin, and leptin) produced from the adipose tissue, and acquisition of somatic mutations in tumor once- and suppressor proteins critical for pancreatic tumorigenesis. In this manuscript, we will explore the broad impact of these obesity-induced risk factors on the development and progression of PDAC, focusing on changes within the tumor microenvironment (TME) as they pertain to prevention, current therapeutic strategies, and future directions for targeting obesity management as they relate to the prevention of pancreatic tumorigenesis.
    Keywords:  Genetic alteration; Insulin resistance; Obesity; Pancreatic ductal adenocarcinoma; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.semcancer.2023.11.002
  22. Cancer Immunol Res. 2023 Nov 06.
    Notch signaling regulates immunosuppressive tumor-associated macrophage function in pancreatic cancer.
    Wei Yan, Rosa E Menjivar, Monica E Bonilla, Nina G Steele, Samantha B Kemp, Wenting Du, Katelyn L Donahue, Kristee Brown, Eileen S Carpenter, Faith R Avritt, Valerie M Irizarry-Negron, Sion Yang, William R Burns, Yaqing Zhang, Marina Pasca di Magliano, Filip Bednar.
      Pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. The poor survival of patients with PDA has been attributed to a high rate of early metastasis and low efficacy of current therapies, which partly result from its complex immunosuppressive tumor microenvironment. Previous studies from our group and others have shown that tumor-associated macrophages (TAMs) are instrumental in maintaining immunosuppression in PDA. Here, we explored the role of Notch signaling, a key regulator of immune response, within the PDA microenvironment. We identified Notch pathway components in multiple immune cell types within human and mouse pancreatic cancer. TAMs, the most abundant immune cell population in the tumor microenvironment, expressed high levels of Notch receptors, with cognate ligands such as JAG1 expressed on tumor epithelial cells, endothelial cells, and fibroblasts. TAMs with activated Notch signaling expressed higher levels of immunosuppressive mediators, suggesting that Notch signaling plays a role in macrophage polarization within the PDA microenvironment. Genetic inhibition of Notch in myeloid cells led to reduced tumor size and decreased macrophage infiltration in an orthotopic PDA model. Combination of pharmacological Notch inhibition with PD-1 blockade resulted in increased cytotoxic T-cell infiltration, tumor cell apoptosis, and smaller tumor size. Our work implicates macrophage Notch signaling in the establishment of immunosuppression and indicates that targeting the Notch pathway may improve the efficacy of immune-based therapies in PDA patients.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0037
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